KR20080004571A - 2-thioethenyl carbapenem derivative - Google Patents

Abstract

A 2-ethenylthio carbapenem derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof. This compound has a potent antibacterial effect and a broad antibacterial spectrum against pneumococci including penicillin-resistant Streptococcus pneumoniae (PRSP), influenza viruses including beta-lactamase-non-producing ampicillin-resistant Haemophilus influenzae (BLNAR), Moraxella catarrhalis and the like.

Description

2-thioethenyl carbapenem derivatives {2-THIOETHENYL CARBAPENEM DERIVATIVE}

The present application discloses Japanese Patent Application Nos. 2005-114690 (filed April 12, 2005) and Japanese Patent No. 2005-235590 (filed August 16, 2005), the prior US patent provisional application 60 / 673892 (filed April 22, 2005) and 60/710157 (filed August 23, 2005), claiming their priority interests, the entire disclosure of which is hereby incorporated by reference. It is incorporated by this.

Field of technology

The present invention relates to a carbapenem compound having excellent antibacterial activity and a broad antibacterial spectrum. Specifically, the present invention relates to a novel carbapenem derivative having a thioethenylthiazole group at the second position of the carbapenem ring.

Carbapenem derivatives show strong antibacterial activity and excellent antimicrobial spectrum over a wide range, and thus active research has been actively conducted as β-lactam agents having high usefulness, and has already been impenem, panipenem, and merope. Meropenem and Viapenem are used in the clinic.

Groups of compounds using various binding modalities at the second place of the carbapenem ring have been studied (Expert Opinion Therapeutic Patents, (UK), 2001, 11 (8), p1267-1276), among others sulfur at the second place of the carbapenem ring. The study of a group of compounds having heterocyclic rings is carried out via atoms.

For example, Japanese Unexamined Patent Application Publication No. 57-40487 discloses a compound in which the first position of the carbapenem ring is a hydrogen atom and the second has a thioethenyl tetrazole. In Japanese Patent Application Laid-Open No. 08-12675 and Japanese Patent Application Laid-Open No. 08-12676, the first place of the carbapenem ring is a methyl group (also referred to as a "1β-methyl group"), and the thioalkenylene halophenyl group is placed in the second place. Or compounds having thioalkenylenepyridyl groups are disclosed, respectively. Japanese Unexamined Patent Application Publication No. 01-279888 discloses a compound having a methyl group at the fifth position of the carbapenem ring and a side chain having a sulfur atom at the second position.

However, neither of the compounds having a thioethenylthiazole group on the carbapenem ring 2 is disclosed or suggested.

Japanese Patent Laid-Open No. 2002-332288 discloses a cephalosporin-based compound having thioethenylthiazole. However, this includes pneumococcal, including β-lactamase-negative ampicillin-resistant influenza, which is a problem in clinical practice today, which can be abbreviated as penicillin-resistant pneumococci (hereinafter abbreviated as "PRSP"). There is no disclosure or suggestion of antimicrobial activity against influenza bacteria, catalcocci, resistant Pseudomonas aeruginosa, etc.

Japanese Unexamined Patent Publication No. 2002-332288 discloses 4-tritylthioethenylthiazole having a methyl group on the thiazole ring. However, there is no disclosure of thiazole having other substituents, and the preparation thereof is different from that in the present invention. The publication discloses 5-ethynyl-4-methylthiazole, but no thiazole having other substituents is disclosed.

Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin, which are today's major clinical problems, are resistant to enterococci, penicillin-resistant pneumococci (PRSP), and β-lactamase-negative About ampicillin-resistant influenza bacteria (BLNAR) and resistant Pseudomonas aeruginosa, it is difficult to say that there is always sufficient antibacterial activity, and the drug which cannot satisfy is not found.

The carbapenem derivatives and cephalosporin derivatives disclosed in the above-described prior art documents, including various resistant bacteria, are not necessarily satisfied from the viewpoint of antibacterial activity. For this reason, there is still a need to develop a compound having an activity that is satisfactory for various resistant bacteria and infectious agents.

Summary of the Invention

The present inventors have found out that the novel carbapenem derivative represented by the formula (I) has broad and strong antibacterial activity against gram positive bacteria and gram negative bacteria. This derivative exhibited strong antimicrobial activity against influenza bacteria, Moraxella (Branhamella catarrhalis) and β-lactamase acid bacteria. Moreover, the compound of Formula (I) was obtained efficiently by using the compound of Formula (III) and the compound of Formula (IV) as an important synthetic intermediate. The present invention is based on these findings.

The present invention provides a carbapenem derivative having excellent antimicrobial activity and a broad range of antimicrobial spectrum, and more particularly, among pneumococcal bacteria including PRSP, influenza bacteria including BLNAR, catalcocci and β-lactamase among infectious agents. An object of the present invention is to provide a carbapenem derivative having a strong antibacterial activity and a wide range of antibacterial spectrum.

The compound according to the present invention is represented by the following formula (I), and according to the present invention there is also provided a pharmaceutically acceptable salt thereof:

[In the meal,

R ¹ represents a hydrogen atom or a methyl group,

R ² and R ³ may be the same or different, respectively,

Hydrogen atom,

Halogen atom,

Amino Group,

Substituted amino groups,

Lower alkyl group,

Substituted lower alkyl group,

Carbamoyl,

Substituted aminocarbonyl groups,

Lower alkoxycarbonyl group,

Substituted lower alkoxycarbonyl groups,

Heterocyclic carbonyl group, or

Substituted heterocyclic carbonyl groups

Indicates,

R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo.

According to a preferred embodiment of the invention, the compound of formula (I) is a compound of formula (II)

[In the meal,

R ¹ represents a hydrogen atom or a methyl group,

Ring A is

  4-hydroxymethylthiazole,

  5-hydroxymethylthiazole,

  4- (2-hydroxyethoxy) methylthiazole,

  4-N, N-dimethylcarbamoylthiazole,

  2-N, N-dimethylcarbamoylthiazole,

  4-methylthiazole,

  4-carbamoylthiazole,

  2-carbamoylthiazole,

  4-N-methylcarbamoylthiazole,

  4-N-cyanomethyl-N-methylcarbamoylthiazole,

  4-N-cyanomethylcarbamoylthiazole,

  4-N- (2-cyanoethyl) carbamoylthiazole,

  4-cyanomethylthiazole,

  4- (2-methoxyethoxy) methylthiazole,

  4- (3-cyanoazetidin-1-yl) carbonylthiazole,

  4-N- (2-hydroxyethyl) carbamoylthiazole,

  4-N- (3-hydroxypropan-1-yl) carbamoylthiazole,

  4-N- (2-hydroxyethyl) -N-methylcarbamoylthiazole,

  4- (azetidin-1-yl) carbonylthiazole,

  4- (3-hydroxyazetidin-1-yl) carbonylthiazole,

  4- (3-hydroxypropan-1-yloxy) methylthiazole,

  2-amino-4-carbamoylthiazole,

  2-aminothiazole,

  4,5-dicarbamoylthiazole,

  4-acetoxymethylthiazole,

  4- (2-acetoxyethoxy) methylthiazole,

  4- (L-valyloxymethyl) thiazole,

  4-methoxycarbonylthiazole,

  4-ethoxycarbonylthiazole,

  2-amino-4-methoxycarbonylthiazole, or

  2-amino-4-ethoxycarbonylthiazole

Indicates,

R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo.

According to another aspect of the invention, as a synthetic intermediate of the compound of formula (I), there is provided a compound of formula (III), or a pharmaceutically acceptable salt thereof:

[In the meal,

One of R ^{2 ′} , and R ^{3 ′} is

  Hydroxy lower alkyl group,

  A hydroxy lower alkyl group protected by a protecting group of a hydroxy group,

  Lower alkoxy-lower alkyl group, or

  Lower alkoxycarbonyl group

And the other is a hydrogen atom,

R ⁵ represents a hydrogen atom or a protecting group of an alkynyl group.

According to another embodiment of the invention, as a synthetic intermediate of the compound of formula (I), there is provided a compound of formula (IV), or a pharmaceutically acceptable salt thereof:

[In the meal,

R ^{2 '} and R ^3' are the same or different, respectively,

  Hydrogen atom,

  Halogen atom,

  Amino Group,

  Substituted amino groups,

  Hydroxy lower alkyl group,

  Cyano lower alkyl group,

  Lower alkoxy-lower alkyl groups,

  Substituted lower alkoxy-lower alkyl group,

  Lower alkoxy-lower alkoxy-lower alkyl groups,

  Substituted lower alkoxy-lower alkoxy-lower alkyl group,

  Acyloxy lower alkyl group,

  Substituted acyloxy lower alkyl groups,

         Carbamoyl,

  Mono-lower alkylcarbamoyl groups,

  Substituted mono-lower alkylcarbamoyl groups,

  Di-lower alkylcarbamoyl groups,

  Substituted di-lower alkylcarbamoyl groups,

  Lower alkoxycarbonyl group,

  Azetidinylcarbonyl group, or,

  Substituted azetidinylcarbonyl groups

Indicates,

R ⁶ is

R ⁷ -SC = C-

Wherein R ⁷ represents a protecting group of a hydrogen atom, a metal ion, or a thiol.

Moreover, according to this invention, the manufacturing method of a compound of Formula (I) is provided. This method is characterized by reacting a compound of formula (V) with a compound of formula (IVc):

[In the meal,

R ¹ represents a hydrogen atom or a methyl group,

R ⁸ represents a hydrogen atom or a protecting group of a hydroxy group,

R ⁹ represents a protecting group of a carboxyl group, and

L represents a leaving group;

[In the meal,

R ⁷ represents a metal ion,

R ^{2 '} and R ^3' are the same or different, respectively,

  Hydrogen atom,

  Halogen atom,

  Amino Group,

  Substituted amino groups,

  Hydroxy lower alkyl group,

  Cyano lower alkyl group,

  Lower alkoxy-lower alkyl groups,

  Substituted lower alkoxy-lower alkyl group,

  Lower alkoxy-lower alkoxy-lower alkyl groups,

  Substituted lower alkoxy-lower alkoxy-lower alkyl group,

  Acyloxy lower alkyl group,

  Substituted acyloxy lower alkyl groups,

  Carbamoyl,

  Mono-lower alkylcarbamoyl groups,

  Substituted mono-lower alkylcarbamoyl groups,

  Di-lower alkylcarbamoyl groups,

  Substituted di-lower alkylcarbamoyl groups,

  Lower alkoxycarbonyl group,

  Azetidinylcarbonyl group, or,

  Substituted azetidinylcarbonyl groups

].

According to a preferred embodiment of the present invention, the process for preparing the compound of formula (I) further comprises reacting the compound of formula (III) with a corresponding thiol represented by formula R ^7b SH to obtain a compound of formula (IVc) Obtained compound includes:

[In the meal,

One of R ^{2 '} and R ^3' is

  Hydroxy lower alkyl group,

  A hydroxy lower alkyl group protected by a protecting group of a hydroxy group,

  Lower alkoxy-lower alkyl group, or

  Lower alkoxycarbonyl group

And the other is a hydrogen atom,

R ⁵ represents a hydrogen atom or a protecting group of an alkynyl group, and

Wherein R ^7b in the corresponding thiol is a group selected from the group consisting of a triphenylmethyl group, a diphenylmethyl group, an acyl protecting group, an optionally substituted benzyl group, and a silyl protecting group.

The pharmaceutical composition according to the present invention comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention. Preferably the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention and a pharmaceutically acceptable carrier. More preferably, this pharmaceutical composition is used as an antimicrobial agent.

According to another aspect of the invention, a bacterial infection or related thereto, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention Methods of treating or preventing symptoms are provided. Preferably, the bacterium is selected from the group consisting of pneumococci, influenza bacteria, catalcocci and β-lactamase acid bacteria.

According to another aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention for the manufacture of a medicament for the treatment or prophylaxis of bacterial infections or symptoms related thereto. do.

The carbapenem derivative of the formula (I) according to the present invention has a broadly strong antibacterial activity against gram positive bacteria and gram negative bacteria. In particular, it has a strong antibacterial activity against various pathogens, including pneumococci, including PRSP, influenza bacteria, including BLNAR, catalcocci and β-lactamase acid bacteria. Among the compounds of formula (I) according to the present invention, carbapenem derivatives of formula (I), which is a group in which R ⁴ is hydrolyzed in vivo, exhibit oral absorptivity, and are metabolically deesterified in vivo to prevent antibacterial activity. To produce an active compound (a compound of formula (I ')). For this reason, the compound of the formula (I) of the present invention is useful not only as an injection but also its ester as an oral preparation. The carbapenem derivatives according to the present invention are low toxicity and high in safety.

Detailed description of the invention

Justice

In the present specification, the term "lower alkyl group" or "lower alkoxy group" as part of a group or group means an alkyl group or an alkoxy group having 1 to 6, preferably 1 to 4 carbon atoms, each linear or branched.

Examples of "lower alkyl" as a group or part of a group include methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, 1 -Pentyl, t-pentyl, n-hexyl, 1-hexyl and the like.

Moreover, as an example of "lower alkoxy" as a group or a part of group, methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentyl Oxy, neopentyloxy, 1-pentyloxy, t-pentyloxy, n-hexyloxy, 1-hexyloxy and the like.

As used herein, the term "lower cycloalkyl group" as part of a group or group means an alkyl group having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Examples of the "acyl group" as a part of the group or group include a formyl group, an acetyl group, propionyl group, butyryl group, pivaloyl group, isobutyryl group, valeryl group, benzoyl group, phthaloyl group, arylcarbonyl group, Heterocyclic carbonyl group etc. are mentioned.

In this specification, a "halogen atom" represents atoms, such as fluorine, chlorine, bromine, and iodine. Preferably the halogen atom is a chlorine atom or bromine atom.

In this specification, a "aryl group" as a part of a group or group means a phenyl group, a naphthyl group, etc.

As used herein, "heterocyclic" as a group or part of a group is the same or different, and is a 4 to 7 membered ring having one or a plurality of heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur (preferably Is a 5-6 membered ring) heterocyclic. Preferably, as the heterocyclic, furan, pyrrole, imidazole, pyrazole, thiazole, triazole, thiadiazole, pyridine, pyrazine, pyridazine, pyrimidine, isoxazole, thiophene, azetidine, Pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, thiazolin, and the like, more preferably furan, thiophene, imidazole, thiazole, pyridine, pyrimidine, azetidine, pyrroli Dine, piperidine, piperazine, morpholine, thiazolin and the like.

compound

R ¹ represents a hydrogen atom or a methyl group. According to one preferred embodiment of the invention, R ¹ is a methyl group.

R ² and R ³ , and R ^{2 ′} and R ^{3 ′,} are the same or different and represent a hydrogen atom, a halogen atom, an amino group, a substituted amino group, a lower alkyl group, a substituted lower alkyl group, a carbamoyl group, a substituted aminocarbonyl group, Lower alkoxycarbonyl groups, substituted lower alkoxycarbonyl groups, heterocyclic carbonyl groups, or substituted heterocyclic carbonyl groups.

Here, as a substituent of an amino group in a "substituted amino group" and a "substituted aminocarbonyl group", a lower alkyl group, a lower cycloalkyl group, a lower alkoxy group, a lower alkoxyalkyl group, a lower alkylcarbonyl group, a lower alkoxycarbonyl group, a formyl group, an aminocarbonyl group And an aminosulfonyl group, a lower alkyl carbamoyl group, a hydroxy lower alkyl group, an amino lower alkyl group, an aryl group, or a heteroaryl group.

"Substituted lower alkyl group", "substituted lower alkoxycarbonyl group", "substituted lower alkoxycarbonyl group", "substituted lower alkoxy-lower alkyl group", "substituted lower alkoxy-lower alkoxy-lower alkyl group", "substituted mono Substituents of the "lower alkyl group" in the "lower alkyl carbamoyl group" and the "substituted di-lower alkyl carbamoyl group" and the "lower alkyl group" which is part of the group include a hydroxy group, a lower alkoxy group, a lower alkylthio group, An amino group, an aryl group, a heterocyclic group, a carbamoyl group, a lower alkylaminocarbonyl group, a formamino group, a lower alkylcarbonylamino group, an aminosulfonylamino group, an aminocarbonylamino group, etc. are mentioned.

As a substituent of the heterocyclic ring in a "substituted heterocyclic carbonyl group", a hydroxyl group, an amino group, a lower alkyl group, a lower alkoxy group, etc. are mentioned.

Preferred groups of R ² and R ³ and R ^{2 '} and R ^3' include a hydrogen atom, a halogen atom, an amino group, a substituted amino group, a lower alkyl group, a hydroxy lower alkyl group, a hydroxy lower alkyl group protected with a protecting group of a hydroxy group, Cyano lower alkyl group, lower alkoxy-lower alkyl group, substituted lower alkoxy-lower alkyl group, lower alkoxy-lower alkoxy-lower alkyl group, substituted lower alkoxy-lower alkoxy-lower alkyl group, acyloxy lower alkyl group, substituted acyloxy lower alkyl group , Carbamoyl group, mono-lower alkylcarbamoyl group, substituted mono-lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, substituted di-lower alkylcarbamoyl group, lower alkoxycarbonyl group, azetidinylcarbonyl group, Substituted azetidinylcarbonyl group etc. are mentioned.

In the present specification, as the protecting group of the hydroxy group, a silyl protecting group, methyl group, methoxymethyl group, aryl group, benzyl group, aryloxycarbonyl group, t-butoxycarbonyl group, optionally substituted benzyloxycarbonyl group, acyl group, etc. Examples thereof include trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, aryloxycarbonyl group, t-butoxycarbonyl group, 4-nitrobenzyloxycarbonyl group, and 4-methoxybenzyloxycarbonyl group. Can be mentioned.

More preferably, as R ² and R ³ and R ^{2 '} and R ^3' , a hydrogen atom, a halogen atom, an amino group, a methyl group, an ethyl group, a propyl group, a cyanomethyl group, a hydroxymethyl group, a hydroxyethyl group, ace Methoxymethyl group, (2-hydroxyethoxy) methyl group, (3-hydroxypropyloxy) methyl group, (2-methoxyethoxy) methyl group, (2-acetoxyethoxy) methyl group, L-valyloxymethyl group, cover Moyl group, N-methyl carbamoyl group, N-cyanomethyl carbamoyl group, N- (2-cyanoethyl) carbamoyl group, N- (2-hydroxyethyl) carbamoyl group, N- (3- Hydroxypropyl) carbamoyl group, N, N-dimethylcarbamoyl group, N- (2-hydroxyethyl) -N-methylcarbamoyl group, N-cyanomethyl-N-methylcarbamoyl group, methoxycarbonyl group , Ethoxycarbonyl, (azetidin-1-yl) carbonyl group, (3-cyanoazetidin-1-yl) carbonyl group, (3-hydroxyazetidin-1-yl) carbonyl group, and the like.

According to a further preferred embodiment of the invention, ring A in formula (II) is 2-hydroxymethylthiazole, 4-hydroxymethylthiazole, 5-hydroxymethylthiazole, 4- (2-hydroxy Ethoxy) methylthiazole, 2-N, N-dimethylcarbamoylthiazole, 4-N, N-dimethylcarbamoylthiazole, 5-N, N dimethylcarbamoylthiazole, 4-methylthiazole, 2- Carbamoylthiazole, 4-carbamoylthiazole, 5-carbamoylthiazole, 4-N-methylcarbamoylthiazole, 4-N-cyanomethyl-N-methylcarbamoylthiazole, 4-N-sia Nomethylcarbamoylthiazole, 4-N- (2-cyanoethyl) carbamoylthiazole, 4-cyanomethylthiazole, 4- (2-methoxyethoxy) methylthiazole, 4- (3- Cyanoazetidin-1-yl) carbonylthiazole, 4-N- (2-hydroxyethyl) carbamoylthiazole, 4-N- (3-hydroxypropan-1-yl) carbamoylthiazole, 4-N- (2-hydroxyethyl) -N-methylcarbamoylthiazole, 4- (azetidin-1-yl) carbonylthiazole, 4- (3-hydroxyazetidin-1-yl) car Bonylthiazole, 4- (3- Hydroxypropan-1-yloxy) methylthiazole, 2-amino-4-carbamoylthiazole, 2-aminothiazole, 4,5-dicarbamoylthiazole, 4-acetoxymethylthiazole, 4- (2-acetoxyethoxy) methylthiazole, 4- (L-valyloxymethyl) thiazole, 4-methoxycarbonylthiazole, 4-ethoxycarbonylthiazole, 2-amino-4-methoxy Carbonylthiazole, 2-amino-4-ethoxycarbonylthiazole and the like.

R ⁴ is a hydrogen atom or a group that is hydrolyzed in vivo. In addition, R <^4>' is synonymous with the group hydrolyzed in vivo of R <^4> .

When R ⁴ is a group hydrolyzed in vivo, the group is preferably an ester moiety, for example, a lower alkyl group, a lower alkenyl group, a lower alkylcarbonyloxy-lower alkyl group, a lower cycloalkylcarbonyloxy-lower alkyl group , Lower cycloalkylmethylcarbonyloxy-lower alkyl group, lower alkenylcarbonyloxy-lower alkyl group, arylcarbonyloxy lower alkyl group, tetrahydrofuranylcarbonyloxymethyl group, lower alkoxy-lower alkyl group, lower alkoxy-lower alkoxy- Lower alkyl group, arylmethyloxy lower alkyl group, arylmethyloxy-lower alkoxy-lower alkyl group, lower alkoxycarbonyloxy lower alkyl group, lower alkoxycarbonyloxy-lower alkoxy group, lower cycloalkoxycarbonyloxy-lower alkyl group, lower cycloalkyl Methoxycarbonyloxy-lower alkyl group, aryloxycarbonyloxy lower alkyl group, optionally substituted on an aromatic ring 3-phthalidyl group having, optionally 2- (3-phthalidylidene) ethyl group having a substituent on the aromatic ring, 2-oxotetrahydrofuran-5-yl group, mono-lower alkylaminocarbonyloxymethyl group, di Lower alkylaminocarbonyloxymethyl groups, 2-oxo-5-lower alkyl-1,3-dioxolen-4-ylmethyl groups, optionally substituted piperidinylcarbonyloxy lower alkyl groups, or lower alkyl-lower cycloalkylamino Commonly used things, such as a carbonyloxy lower alkyl group, are mentioned.

Preferably, R ⁴ is a methyl group, an ethyl group, a 1- (cyclohexyloxycarbonyloxy) ethyl group, an acetoxymethyl group, a 1- (isopropyloxycarbonyloxy) ethyl group, 1- (ethoxycarbonyloxy) Ethyl group, pivaloyl oxymethyl group, cyclohexyloxycarbonyloxymethyl group, 1- (isobutyloxycarbonyloxy) ethyl group, 1- (cyclohexyloxycarbonyloxy) -2-methylpropan-1-yl group, Isobutyloxycarbonyloxymethyl group, isopropyloxycarbonyloxymethyl group, isobutyryloxymethyl group, (pentan-1-yl) oxycarbonyloxymethyl group, (butan-1-yl) oxycarbonyloxymethyl group, (1 -Ethylpropan-1-yl) oxycarbonyloxymethyl group, isopentyloxycarbonyloxymethyl group, (propan-1-yl) oxymethyl group, ethoxycarbonyloxymethyl group, neopentyloxycarbonyloxymethyl group, methoxycarbon Bonyloxymethyl group, cyclopentyloxycarbonyloxymethyl group, t-butoxycarbonyloxy Tyl group, phthalidyl group, 1- (methoxycarbonyloxy) ethyl group, 1- (cyclopentyloxycarbonyloxy) ethyl group, (tetrahydropyran-4-yl) oxycarbonyloxymethyl group, 1- (neopentyloxy Carbonyloxy) ethyl group, (piperidin-1-yl) carbonyloxymethyl group, aryl group, 1- (t-butoxycarbonyloxy) ethyl group, (N, N-di-n-propylamino) carbonyl Oxymethyl group, phenyloxycarbonyloxymethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group, (cis-2,6-dimethylpiperidin-1-yl) carbonyl Oxymethyl group, N, N-di- (butan-1-yl) aminocarbonyloxymethyl group, hexane-1-yl group, N- (hexane-1-yl) -N-methylaminocarbonyloxymethyl group, N, N -Diisobutylaminocarbonyloxymethyl group, N, N-diisopropylaminocarbonyloxymethyl group, N-cyclohexyl-N-methylaminocarbonyloxymethyl group, N-pentan-1-ylaminocarbonyloxymethyl group, N-cyclohexyl-N-ethylaminocarbonyloxymethyl group, N-isobutyl-N-isopropylaminocarbonyloxymethyl group, Nt-butyl-N-ethylaminocarbonyloxymethyl group, 1-[(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy ] Ethyl group, 1- (N, N-diisopropylaminocarbonyloxy) ethyl group, or N-ethyl-N-isoamylaminocarbonyloxymethyl group.

R ⁵ represents a hydrogen atom or a protecting group of alkynyl.

R ⁶ Represents R ⁷ -SC = C-, wherein R ^{7 is} Silver represents a protecting group of a hydrogen atom, a metal ion, or a thiol.

Examples of the protecting group for the alkynyl group of R ⁵ include a silyl protecting group and a 2- (2-hydroxypropyl) group, and preferably a trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, and the like. .

Examples of the metal ions of R ⁷ include alkali metal ions, alkaline earth metal ions, mercury ions, copper ions, silver ions, iron ions, and the like, and lithium ions, sodium ions, potassium ions, silver ions, and mercury. Ions and the like. R ^7c Means the metal ion of R <^7> , and has the same meaning.

The protecting group of the thiol of R ^{7 includes} a triphenylmethyl group, a diphenylmethyl group, an acyl protecting group (for example, an acetyl group, a benzoyl group, a trifluoroacetyl group), an optionally substituted benzyl group, and a silyl protecting group. Etc. are mentioned, Preferably, they are a triphenylmethyl group, an acetyl group, a benzoyl group, 4-methoxybenzyl group, etc. In addition, R <^7b> means the protecting group of the thiol of R <^7> , and has the same meaning.

Examples of the protecting group for the hydroxyl group of R ⁸ include a silyl group, a methyl group, a methoxymethyl group, an aryl group, a benzyl group, an aryloxycarbonyl group, t-butoxycarbonyl group, an optionally substituted benzyloxycarbonyl group, and an acyl group. Preferable examples thereof include trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, aryloxycarbonyl group, t-butoxycarbonyl group, 4-nitrobenzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group and the like.

Examples of the protecting group for the carboxyl group of R ⁹ include a lower alkyl group, an optionally substituted benzyl group, a silyl protecting group, an aryl group, a triphenylmethyl group, a diphenylmethyl group, and the like, and preferably a methyl group, t-butyl group, Benzyl group, 4-methoxybenzyl group, 4-nitrobenzyl group, aryl group and the like.

L is a leaving group, for example, a halogen atom, a lower alkylsulfonyloxy group, an optionally substituted arylsulfonyloxy group, a perfluoroalkanesulfonyloxy group, a fluorosulfonyloxy group, a lower alkylsulphenyl group, an optionally substituted arylsul A phenyl group, heterocyclic sulfenyl group, a diphenylphosphoryloxy group, etc. are mentioned, Preferably, a methanesulfonyloxy group, a toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, a diphenylphosphoryloxy group, etc. are mentioned. Can be.

R <^10> represents a hydrogen atom and a metal ion, Preferably, they are a hydrogen atom, sodium ion, potassium ion, etc.

Salts of general formula (I) are pharmaceutically acceptable salts, for example inorganic salts such as lithium, sodium, potassium, calcium, magnesium; Or ammonium salts; Salts with organic bases such as triethylamine salt and diisopropylethylamine salt; Or salts of mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid; Or salts of organic acids such as acetic acid, carbonic acid, citric acid, malic acid, oxalic acid and methanesulfonic acid. Preferably, the salt is a sodium salt, potassium salt, or hydrochloride.

And the compound according to the present invention can form a solvate. As such a solvate, a hydrate, alcoholate (for example, methanolate, ethanolate), and etherate (for example, diethyl etherate) are mentioned.

According to one preferred embodiment of the invention,

In formula (III), one of R ^{2 '} and R ^3' is

  Hydroxymethyl group,

  Acetoxymethyl group,

  Methoxycarbonyl group,

  Ethoxycarbonyl group,

And the other is a hydrogen atom.

According to one preferred embodiment of the invention,

In formula (IV), one of R ^{2 '} and R ^3' is

  Hydroxy lower alkyl group,

  A hydroxy lower alkyl group protected by a protecting group of a hydroxy group,

  Lower alkoxy-lower alkyl group, or

  Lower alkoxycarbonyl group

And the other represents a hydrogen atom.

According to one more preferred embodiment of the present invention,

In formula (IV), one of R ^{2 '} and R ^3' is

  Hydroxymethyl group,

  Acetoxymethyl group,

  Methoxycarbonyl group, or

  Ethoxycarbonyl group,

And the other represents a hydrogen atom.

According to one preferred embodiment of the invention, R ⁶ is on the thiazole ring 5 of formula (IV).

Next, specific examples of the carbapenem derivatives of the general formula (I) and intermediates thereof according to the present invention are illustrated, but the present invention is not limited thereto. On the other hand, the number described before the compound name below means a compound number.

1. 4-hydroxymethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

2. 4- (2-hydroxyethoxy) methyl-5-((Z) -2-tritylthioethen-yl) thiazole

3. 4-N, N-dimethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

4. 4-hydroxymethyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

5. 4-Methyl-5-((Z) -2-tritylthioethen-yl) thiazole

6. 4-carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

7. 4-N-methylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

8. 4-N-cyanomethyl-N-methylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl)

Thiazole

9. 4-N-cyanomethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

10. 4-N- (2-cyanoethyl) carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

11.4-cyanomethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

12. 4- (2-methoxyethoxy) methyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

13. 4- (3-cyanoazetidin-1-yl) carbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

14. 4-N- (2-hydroxyethyl) carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

15. 4-N- (3-hydroxypropan-1-yl) carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

16. 4-N- (2-hydroxyethyl) -N-methylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

17. 4- (azetidin-1-yl) carbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

18. 4- (3-hydroxyazetidin-1-yl) carbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

19. 4- (3-hydroxypropan-1-yloxy) methyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

20. 2-Amino-4-carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

21. 4-hydroxymethyl-5-((E) -2-tritylthioethen-1-yl) thiazole

22. 2-Carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

23. 2-amino-5-((Z) -2-tritylthioethen-1-yl) thiazole

24. 2-N, N-dimethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

25. 4-carbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

26. 4-N- (2-hydroxyethyl) carbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

27. 4-N, N-dimethylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

28. 4-N-methylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

29. 4-N-cyanomethylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

30. 4-N-cyanomethyl-N-methylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

31.4-Cyanomethyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

32. 4- (3-hydroxyazetidin-1-yl) carbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

33. 4- (3-cyanoazetidin-1-yl) carbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

34. 5-hydroxymethyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

35. 4,5-Dicarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

36. 4-((Z) -2-tritylthioethen-1-yl) thiazole

37. 2-Carbamoyl-4-((Z) -2-tritylthioethen-1-yl) thiazole

38. 5-hydroxymethyl-4-((Z) -2-tritylthioten-1-yl) thiazole

39. 4-ethoxycarbonyl-5- (2-trimethylsilylethynyl) thiazole

40. 4-Ethoxycarbonyl-5-ethynylthiazole

41. Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene- 1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

42. Sodium (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -6 -((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

43. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6- ( (1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

44. Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-2-yl) ethene- 1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

45. Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4-methylthiazol-5-yl) Ethen-1-yl] thio] -1-carbafen-2-m-3-carboxylate

46. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1 -Hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

47. Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4-N-methylcarbamoylthiazole- 5-yl) ethen-1-yl] thio] -1-carbafen-2-m-3-carboxylate

48. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N-cyanomethyl-N-methylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

49. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N-cyanomethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6- ( (1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

50. Sodium (1R, 5S, 6S) -2-[[(Z) -2- [4-N- (2-cyanoethyl) carbamoylthiazol-5-yl] ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m 3-carboxylate

51. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-cyanomethylthiazol-5-yl) ethen-1-yl] thio] -6-((1R)- 1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

52. Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4- (2-methoxyethoxy) methylthiazole- 5-yl] ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

53. Sodium (1R, 5S, 6S) -2-[[(Z) -2- [4- (3-cyanoazetidin-1-yl) carbonylthiazol-5-yl] ethen-1-yl ] Thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

54. Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) carbamoylthia Sol-5-yl] ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

55. Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (3-hydroxypropan-1-yl ) Carbamoylthiazol-5-yl] ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

56. Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) -N- Methylcarbamoylthiazol-5-yl] ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

57. Sodium (1R, 5S, 6S) -2-[[(Z) -2- [4- (azetidin-1-yl) carbonylthiazol-5-yl] ethen-1-yl] thio]- 6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

58. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4- (3-hydroxyazetidin-1-yl) carbonylthiazol-5-yl) ethen-1-yl ] Thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

59. Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4- (3-hydroxypropan-1-yloxy) Methylthiazol-5-yl] ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

60. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (2-amino-4-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-(( 1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

61. Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(E) -2- (4-hydroxymethylthiazol-5-yl) ethene- 1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

62. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (2-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1 -Hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

63. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (2-aminothiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1- Hydroxyethyl) -1-methyl-1-carbaphen-2-m-3-carboxylate

64. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (2-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6- ( (1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

65. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-carbamoylthiazol-2-yl) ethen-1-yl] thio] -6-((1R) -1 -Hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

66. Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) carbamoylthia Zol-2-yl] ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

67. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-2-yl) ethen-1-yl] thio] -6- ( (1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

68. Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4-N-methylcarbamoylthiazole- 2-yl) ethen-yl] thio] -1-carbafen-2-m-3-carboxylate

69. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N-cyanomethylcarbamoylthiazol-2-yl) ethen-1-yl] thio] -6- ( (1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

70. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N-cyanomethyl-N-methylcarbamoylthiazol-2-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

71. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-cyanomethylthiazol-2-yl) ethen-1-yl] thio] -6-((1R)- 1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

72. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4- (3-hydroxyazetidin-1-yl) carbonylthiazol-2-yl) ethen-1-yl ] Thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

73. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4- (3-cyanoazetidin-1-yl) carbonylthiazol-2-yl) ethen-1-yl ] Thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

74. Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (5-hydroxymethylthiazol-2-yl) ethene- 1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

75. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4,5-dicarbamoylthiazol-2-yl) ethen-1-yl] thio] -6-((1R ) -1-hydroxyethyl) -1-methyl-1-carbaphen-2-m-3-carboxylate

76. Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (thiazol-4--yl) ethene- 1-yl] thio] -1-carbafen-2-m-3-carboxylate

77. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (2-carbamoylthiazol-4-yl) ethen-1-yl] thio] -6-((1R) -1 -Hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

78. Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (5-hydroxymethylthiazol-4-yl) ethene- 1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

79. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-acetoxymethylthiazol-5-yl) ethen-1-yl] thio] -6-((1R)- 1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

80. Sodium (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-acetoxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -6 -((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

81. 1- (Cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy) methylthiazol-5-yl ] Ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

82. 1- (Cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-5-yl) ethene -1-yl] thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

83. 1- (Cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Roxymethylthiazol-2-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

84. 1- (Cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[[(Z) -2- (4-carbamoylthiazol-5-yl) ethen-1-yl] Thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

85. 1- (Cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[[(Z) -2- (4-N-cyanomethylcarbamoylthiazol-5-yl) ethene -1-yl] thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

86. 1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N -(2-hydroxyethyl) carbamoylthiazol-5-yl] ethen-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

87. Pivaloyloxymethyl (1R, 5S, 6S) -2-[[(Z) -2- (2-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-(( 1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

88. 1- (Cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N -(2-hydroxyethyl) carbamoylthiazol-2-yl] ethen-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

89. 1- (Cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Roxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

90. Acetoxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) Eten-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

91. 1- (Isopropyloxycarbonyloxy) ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Methylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

92. 1- (Ethoxycarbonyloxy) ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethyl Thiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

93. Pivaloyl oxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5- Yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

94. Cyclohexyloxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole -5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

95. 1- (Isobutyloxycarbonyloxy) ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Methylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

96. 1- (Cyclohexyloxycarbonyloxy) -2-methylpropan-1-yl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z ) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

97. Isobutyloxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole- 5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

98. Isopropyloxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole- 5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

99. Isobutyryloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5- Yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

100. (pentan-1-yl) oxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Roxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

101. (Butan-1-yl) oxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Roxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

102. (1-Ethylpropan-1-yl) oxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- ( 4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

103. Isopentyloxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole- 5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

104. (Propan-1-yl) oxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Roxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

105. 1- (cyclohexyloxycarbonyloxy) ethyl (1R, 5S, 6S) -2-[[(Z) -2- (4-acetoxymethylthiazol-5-yl) ethen-1-yl ] Thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

106.Ethoxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 -Yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

107. Neopentyloxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole- 5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

108. Methoxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 -Yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

109. Cyclopentyloxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole- 5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

110. t-butoxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole -5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

111. Phthalidyl (1R, 5S, 68) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) Eten-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

112. 1- (methoxycarbonyloxy) ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethyl Thiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

113. 1- (cyclopentyloxycarbonyloxy) ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Methylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

114. (Tetrahydropyran-4-yl) oxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4 -Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

115. 1- (Neopentyloxycarbonyloxy) ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Methylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

116. (Piperidin-1-yl) carbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

117. Allyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene- 1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

118. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (L-variinyloxymethyl) thia Sol-5-yl) ethen-yl] thio] -1-carbafen-2-m-3-carboxylate

119. 1- (t-butoxycarbonyloxy) ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Roxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

120. 1- (t-butoxycarbonyloxy) ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Roxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

121. Ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene- 1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

122. (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[( Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

123.Phenyloxycarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 -Yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

124. N, N-di (propan-1-yl) aminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2 -(4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

125. (Cis-2,6-dimethylpiperidin-1-yl) carbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z ) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

126.N, N-di- (butan-1-yl) aminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z)- 2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

127. Hexane-1-yl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5- Yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylic acid

128.N- (hexane-1-yl) -N-methylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z)- 2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

129.N, N-diisobutylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Roxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

130. N, N-diisopropylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Roxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

131.N-cyclohexyl-N-methylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

132.N-pentan-1-ylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Roxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

133.N-cyclohexyl-N-ethylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

134.N-isobutyl-N-isopropylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4 -Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

135. Nt-butyl-N-ethylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Roxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

136. 1- (N, N-diisopropylaminocarbonyloxy) ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (diastereomer mixture)

137. 1-[(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate (dia Stereomer mixture)

138.N-ethyl-N-isoamylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

139. (5-Bromothiazol-4-yl) methanol

140. [5- [2- (trimethylsilyl) ethynyl] thiazol-4-yl] methanol

141. 5-Ethynyl-4-hydroxymethylthiazole

142.N, N-diisopropylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Roxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

143. Sodium (5R, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1- Yl] thio] -1-carbafen-2-m 3-carboxylate

144.N, N-diisopropylaminocarbonyloxymethyl (5R, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethyl Thiazol-5-yl) ethen-1-yl] thio] -1-carbafen-2-m-3-carboxylate

145. (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene-1 -Yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylic acid

146. Potassium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene- 1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

147.N, N-diisopropylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(E) -2- (4-hydroxy Oxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate.

Preparation of Compound

The compound according to the present invention can be produced, for example, according to the following scheme. Starting materials required for the synthesis of the compounds according to the invention are commercially available or can be readily prepared by conventional methods.

Among the compounds of the formula (I) according to the present invention, a compound in which R ⁴ is a hydrogen atom, or a compound of formula (I '), which is a salt thereof, is preferably produced according to the following scheme.

Scheme 1

[In the said scheme, R <^1> , R <^2> and R <^3> represent the same meaning as what was defined by said Formula (I), and R < ^7b Is the same as the protecting group of thiol as defined in R ⁷ (for example, triphenylmethyl group, acetyl group, benzoyl group, 4-methoxybenzyl group, etc.), and R ^7c Is the same as the metal ion defined in R ⁷ (eg, lithium ion, sodium ion, potassium ion, silver ion, mercury ion, etc.), and R ⁸ is a hydrogen atom or a hydroxyl protecting group (eg, t -butyldimethylsilyl group, a trimethylsilyl group, a triethylsilyl group, a 4-nitrobenzyloxycarbonyl group, 4-methoxy-benzyloxycarbonyl group, an aryloxy group, etc. represents a), R ⁹ is a carboxylic protecting group (e. g. 4-nitrobenzyl group, 4-methoxybenzyl group, diphenylmethyl group, t-butyldimethylsilyl group, aryl group, etc.), and R <^10> represents a hydrogen atom or metal ions, such as potassium and sodium. And X represents a halogen atom.]

The compound of formula (IIIa) is a soybean reaction and detrimethylsilylation reaction of thiazole compound of formula (A) having a leaving group such as a halogen atom and trimethylsilylacetylene, or thiazole of formula (A) It can be obtained by a steel coupling reaction of the compound with tributylethynyl tin. Hereinafter R ² or R ³ One of which is a hydroxymethyl group and the other is a hydrogen atom (compound of Formula (d)) is demonstrated as an example.

Scheme 2

[In the above scheme, Ak is methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-butyl, s-butyl, t-butyl, n-pentyl, neopentyl, i-pentyl, t-pentyl, n Lower alkyl groups such as hexyl and i-hexyl.

The compound of the formula (b) may be a suitable solvent (eg, acetonitrile, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, diethyl ether, toluene, benzene, methanol, ethanol, water, or the like, or these Mixed solvent), and a reducing agent such as sodium borohydride, diisobutylaluminum or lithium aluminum hydride is added to the compound of formula (a) at 10 minutes in the presence or absence of lithium chloride, calcium chloride, cerium chloride, or the like. It can obtain by making it react for 72 hours.

Next, the compound of formula (c) may be prepared by using a suitable solvent (for example, acetone, acetonitrile, dichloromethane, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane) with respect to the compound of formula (b). , Diethyl ether, isopropyl ether, hexane, N, N-dimethylformamide, dimethyl sulfoxide, toluene, benzene, methanol, ethanol, triethylamine, hexamethyl phosphate triamide, or a mixed solvent thereof). One equivalent or excess equivalent base (as organic base, for example, triethylamine, diisopropylamine, diisopropylethylamine, pyridine, etc.) As inorganic base, for example, sodium hydroxide, potassium hydroxide, In the presence of sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like, various palladium complexes (e.g., dichloro bis (triphenylphosphine) palladium, bis (benzonitrile) palladium dichloride) Iodide Trivalent phosphine reagents such as li and triphenylphosphine, tributylphosphine, and trifurylphosphine), 1 equivalent or excess equivalent of trimethyl acetylene can be obtained by reacting at -30 ° C to 100 ° C for 10 minutes to 72 hours. have.

Finally, the compound of formula (d) may be prepared by adding a compound of formula (c) to a suitable solvent (eg, acetone, acetonitrile, dichloromethane, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane). Etc.), up to 10 equivalents of acetic acid and tetra n-butylammonium fluoride, or up to 10 equivalents of base (e.g., sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate Etc.) are added and reacted at -80 ° C to 50 ° C for 5 minutes to 24 hours. After the reaction, the compound (d) can be obtained by usual post-treatment.

Moreover, the compound of formula (d) can also be obtained by the method of via the compound of formula (e) and formula (f). The compound of formula (e) can be obtained from the compound of formula (a) by the same method as the process of the compound of formula (c) from the compound of formula (b). Moreover, the compound of Formula (f) can be obtained from the compound of Formula (e) by the method similar to the process of the compound of Formula (d) from the compound of Formula (c) mentioned above. Finally, the step of obtaining the compound of formula (d) from the compound of formula (f) can be obtained by performing the same method as the step of the compound of formula (b) from the compound of formula (a) described above.

The conversion from the compound of formula (IIIa) to the compound of formula (IVb) can be carried out by the following method. That is, the compound of Formula (IVb) can be obtained by making the corresponding thiol react with the ethynylthiazole of Formula (IIIa).

Here, the corresponding thiol is represented by the formula R ^7b SH. The R7 ^b is, as the same meaning as, for example, there may be mentioned triphenylmethane thiol, thio acetic acid, thio-benzo acid, 4-methoxy -α- toluene thiol, etc.

In this case, the R7 ^b is described, for example, when the triphenylmethyl group.

For the compound of formula (IIIa), acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, dioxane, methanol, ethanol, dichloromethane, toluene, hexamethylphosphoric In triamide, water, or the like, or a mixed solvent thereof, one equivalent or excess equivalent of triphenylmethane thiol, and a catalytic amount of base or more (for example, as an organic base, diisopropylethylamine, triethylamine, 2, As inorganic bases, such as 6-lutidine and pyridine, for example, sodium hydride, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate , Potassium carbonate, cesium carbonate and the like), and the reaction is carried out at -80 ° C to + 100 ° C for 5 minutes for 24 hours, whereby the compound of formula (IVb) can be obtained by conventional post-treatment. .

Next, the conversion from the compound of formula (IVb) to the compound of formula (IVc) can be carried out by the following method. Here, the case of silver ion is demonstrated as an example.

That is, 1 equivalent or excess equivalent of pyridine and silver nitrate are added to the compound of formula (IVb), and in a solvent such as THF, acetone, methanol, dichloromethane, chloroform, water, and a mixed solvent thereof, 0 ° C. to + 50 ° C. After reaction at 5 minutes for 8 hours, the compound of formula (IVc) can be obtained by filtration.

In the next step, the conversion from the compound of formula (IVc) to the compound of formula (VI) can be carried out. This conversion can be performed by the following method.

That is, for the compound of formula (IVc) and the compound of formula (V), acetonitrile, acetone, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, dioxane, methanol, ethanol, In dichloromethane, toluene, hexamethylphosphoric triamide and the like, and mixed solvents thereof, at -20 ° C to 100 ° C, one equivalent or excess equivalent of sodium iodide is added to the compound of formula (IVc) as necessary, and 10 After reacting for 3 days in minutes, the compound of formula (VI) can be obtained by usual post-treatment.

On the other hand, a commercial item can be used as a compound of Formula (V) demonstrated above, for example.

Finally, the protecting group of the compound of formula (VI) may be removed by a deprotection reaction according to one step or a plurality of steps, depending on the kind of protecting group, to obtain the compound of formula (I ′) of the present invention.

At this time, the deprotection reaction for removing the protecting group depends on the type of protecting group used, but can be carried out by conventional methods generally known in the art. When either or all can be deprotected under acidic conditions, mineral acids such as hydrochloric acid, organic acids such as formic acid, acetic acid and citric acid, Lewis acids such as aluminum chloride, and the like are reduced. In the case of removal under the following conditions, contact reduction with various catalysts or metal reducing agents such as zinc and iron can be used. Moreover, when R <^8> is a silyl type protecting group (for example, t-butyl dimethyl silyl group, or a trimethyl silyl group, a triethyl silyl group etc.), a fluorine ion reagent (for example, tetrabutyl ammonium fluoride etc.) When R ⁸ is an aryloxycarbonyl group and R ⁹ is an aryl group, it can be easily removed by using various palladium complexes (for example, tetrakis (triphenylphosphine) palladium (0), etc.). have.

The compound of the formula (I ') obtained as described above may be subjected to chromatography using a nonionic macro-high porous resin, gel filtration using Sephadex, or the like, reverse phase silica gel column chromatography, or the like. By using it, it can isolate and refine | purify.

Moreover, among the compounds of general formula (I) which concerns on this invention, the compound of formula (I ") which is group in which R <^4> is hydrolyzed in vivo can be manufactured preferably according to the following scheme.

Scheme 3

[In the scheme, R ¹ , R ² and R ³ Has the same meaning as defined in formula (I) above. R ¹⁰ represents a hydrogen atom or a metal ion such as potassium or sodium, and R ^{4 ′} is a group that is hydrolyzed in vivo (when the group of R ⁴ is hydrolyzed in vivo in the term of the above compound). And X represents a leaving group such as chlorine, bromine, iodine, -OSO ₂ CF ₃ , -OSO ₂ CH ₃ , -OSO ₂ PhCH _3, etc.]

1 equivalent or excess equivalent of base (as an organic base, diisopropylethylamine, diazabicyclo [2,2,2] undecene, 2,6- lutidine as needed with respect to the compound of Formula (I ')). Examples of the inorganic base include sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, and the like, and / or quaternary ammonium salts (for example, triethylbenzyl ammonium chloride, tetraethylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide present under, alkyl halide (R ^{4 '-X} 1 equivalent or excessive amount, such as: X represents a halogen atom, preferably, iodine, bromine, or As chlorine, for example, ethyl iodide, 1- (cyclohexyloxycarbonyloxy) ethyl iodide, bromomethyl acetate, 1- (isopropyloxycarbonyloxy) ethyl iodide, 1- (Ethoxycarbonyloxy) ethyl ah Odoid, iodomethyl pivalate, cyclohexyloxycarbonyloxymethyl iodide, 1- (isobutyloxycarbonyloxy) ethyl iodide, 1- (cyclohexyloxycarbonyloxy) -2 -Methylpropan-1-yl iodide, isobutyloxycarbonyloxymethyl iodide, isopropyloxycarbonyloxymethyl iodide, isobutyloxymethyl iodide, (pentan-1-yl) oxycarbon Bonyloxymethyl iodide, (butan-1-yl) oxycarbonyloxymethyl iodide, (1-ethylpropan-1-yl) oxycarbonyloxymethyl iodide, isopentyloxycarbonyloxymethyl i Odide, (propan-1-yl) oxymethyl iodide, ethoxycarbonyloxymethyl iodide, neopentyloxycarbonyloxymethyl iodide, methoxycarbonyloxymethyl iodide, cyclopentyloxy Carbonyloxymethyl ioda Tert-butoxycarbonyloxymethyl iodide, 3-bromophthalide, 1- (methoxycarbonyloxy) ethyl iodide, 1- (cyclopentyloxycarbonyloxy) ethyl iodide, (Tetrahydropyran-4-yl) oxycarbonyloxymethyl iodide, 1- (neopentyloxycarbonyloxy) ethyl iodide, (piperidin-1-yl) carbonyloxymethyl iodide, Aryl iodide, 1- (t-butoxycarbonyloxy) ethyl iodide, N, N-di (propan-1-yl) aminocarbonyloxymethyl iodide, phenyloxycarbonyloxymethyl iodide Id, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl bromide, (Z) -2- (3-phthalinylidene) ethyl bromide, (cis-2,6- Dimethylpiperidin-1-yl) carbonyloxymethyl chloride, chloromethyl N, N-di-n-butylcarbamate, 1-iodohexane, chloromethyl Nn-hexyl-N-methylcarbamate, chloromethyl N, N- Diisopropylcarbamate, chloromethyl N, N-diisopropylcarbamate, chloromethyl N-cyclohexyl-N-methylcarbamate, chloromethyl N-pentan-1-ylcarbamate, chloromethyl N-cyclohexyl- N-ethylcarbamate, chloromethyl N-isobutyl-N-isopropylcarbamate, chloromethyl Nt-butyl-N-ethylcarbamate, 1-chloroethyl N, N-diisopropylcarbamate, 1-[( cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl chloride, or chloromethyl N-ethyl-N-isoamylcarbamate, etc., alone or in a mixed inert solvent (e.g., N, N-dimethyl formamide, N, N-dimethyl acetamide, N, N-diethyl formamide, N, N-diethyl acetoamide, N-methylpyrrolidinone, N, N-dimethylimidazoridinone , Dimethyl sulfoxide, sulfolane, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, 1,4-dioxane, diethyl ether, anisole, dichloro Methane, 1,2-dichloroethane, chloroform, toluene, benzene, hexamethylphosphorintriamide, methanol, ethanol, etc.) at -70 ° C to + 50 ° C (preferably -30 ° C to + 30 ° C) , The compound of formula (I '') can be obtained by reacting for 10 minutes to 24 hours.

The ester body obtained as mentioned above can be isolate | separated and refine | purified by using gel precipitation, a silica gel column chromatography, reverse phase column chromatography, etc. using precipitation or Sephadex.

Uses / Pharmaceutical Compositions of Compounds

The compound according to the present invention inhibits the growth of pathogens in vitro and exhibits antibacterial activity (see Test Example 1). In addition, it was confirmed that the compound according to the present invention inhibits the growth of pathogens and exhibits antibacterial activity even in the in vivo test. That is, the carbapenem derivative of the formula (I) according to the present invention exhibits strong antimicrobial activity against various pathogens including pneumococci containing PRSP, influenza bacteria including BLNAR, catalcocci and β-lactamase acid bacteria. For this reason, it can be said that the compound by this invention is very effective for the prevention or treatment of the infection by these bacteria or the symptoms related to it.

Therefore, the compound according to the present invention can be used for the prevention or treatment of bacterial infections and symptoms related thereto. Examples of the bacterium causing such fungal infections include those selected from the group consisting of pneumococci, influenza bacteria, catalcocci, and β-lactamase acid bacteria.

According to the present invention there is provided a pharmaceutical composition comprising a compound according to the invention or a pharmacologically acceptable salt thereof. Preferably the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier. The pharmaceutical composition according to the present invention can be used for the prevention or treatment of bacterial infections. That is, it can use as an antibacterial agent.

According to a separate embodiment of the invention, as described above, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to the invention to a patient in need thereof, Methods of treating or preventing bacterial infections or symptoms associated therewith are provided.

As used herein, the term "effective amount" means an amount of an active ingredient that is at least required to exert its effect in order to treat, prevent, suppress the progress of, or improve a disease or symptom or condition. In addition, "patient" refers to a human or a mammal other than humans (for example, mouse, rat, rabbit, dog, cat, cow, horse, pig, monkey, etc.) to which the compound or composition of the present invention is administered. it means. "Administration" means injecting the target substance orally or parenterally into a living body to the target patient.

Moreover, according to this invention, the antibacterial agent which uses the compound by this invention or its pharmacologically acceptable salt as an active ingredient is provided.

The compound according to the present invention or a pharmacologically acceptable salt thereof may be administered by any one of oral and parenteral routes (eg, intravenous administration, intramuscular administration, subcutaneous administration, rectal administration, and transdermal administration). And to animals other than humans.

Therefore, a pharmaceutical composition comprising the compound according to the present invention is formulated in a suitable formulation corresponding to the route of administration. Specifically, oral preparations include tablets, capsules, powdered medicines, granules, pills, fine granules, troches, syrups, and the like. Parenteral preparations include injections, suppositories, and tapes such as intravenous or intramuscular injections. And ointments.

These various preparations include commonly used excipients, extenders, disintegrants, binders, lubricants, colorants, diluents, wetting agents, surfactants, dispersants, buffers, preservatives, dissolution aids, preservatives, corrigents, painless agents, It can manufacture by a conventional method using additives (carriers), such as a stabilizer.

Examples of excipients include lactose, fructose, glucose, corn starch, sorbit, crystalline cellulose, and the like. As disintegrants, for example, starch, sodium alginate, gelatin powder, calcium carbonate, etc. And calcium citrate, dextrin, and the like. Examples of the binder include dimethyl cellulose or salts thereof, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, gelatin, hydroxypropyl cellulose, and polyvinyl pyro. Redon etc. are mentioned. As a lubricant, talc, magnesium stearate, polyethyleneglycol, hardened vegetable oil etc. are mentioned, for example. Other non-toxic additives that can be used include, for example, syrup, petrolatum, lanolin, glycerin, ethanol, propylene glycol, citric acid, sodium chloride, sodium sulfite, sodium phosphate, β-cyclodextrin, hydroxypropyl-β-cyclodextrin , Tween80, and the like.

Moreover, the said injection can be manufactured by adding a buffer, a pH adjuster, a stabilizer, a tonicity agent, a preservative, etc. as needed.

In the pharmaceutical composition according to the present invention, the content of the compound according to the present invention depends on the dosage form, and is usually 0.01 to 100% by weight, preferably 0.1 to 90% by weight, more preferably 0.5 to 50, in the total composition. Weight percent.

The dosage is appropriately determined in response to each case in consideration of the patient's age, weight, sex, type of disease, degree of symptom, and the like, for example, for the treatment of an infectious disease, usually in adult oral administration. As a dosage of about 1 to 2000 mg, preferably 10 to 1000 mg per person, it may be administered once a day or two to six times in response to symptoms.

The compound according to the present invention may be combined with or administered in combination with an organic ion transport inhibitor such as a DHP-1 inhibitor such as cilastin (Dehydrogenas β-1 inhibitor), betamipron, or the like. Can be.

Hereinafter, the present invention will be described with reference to Examples, but the present invention is not limited thereto.

Example  4- Hydroxymethyl -5-((Z) -2- Tritylthioethene -1-yl) thiazole

a) 2-amino-4-ethoxycarbonyl-5-iaodothiazole

A solution of 14.53 g of 2-amino-4-ethoxycarbonylthiazole in 200 ml of THF was ice-cooled under an argon atmosphere, 20.0 g of N-iodosuccinimide was added thereto, and the mixture was stirred at the same temperature for 1.5 hours. It was. Saline was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1: 2) to thereby obtain 2-amino-4-ethoxycarb. 21.12 g of carbonyl-5-iodothiazole were obtained.

b) 4-ethoxycarbonyl-5-iaodothiazole

A solution of 10.68 g of 2-amino-4-ethoxycarbonyl-5-iodothiazole in 140 ml of DMF was ice-cooled under argon atmosphere, 6.15 ml of t-butylnitrite was added, and stirred at room temperature for 30 minutes. The reaction solution was poured into brine, extracted three times with ethyl acetate, and the organic layers were combined and washed three times with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 3: 1) to give 4-ethoxycarbonyl-5-. 5.08 g of aiodotthiazole was obtained.

c) 5-ethynyl-4-methoxycarbonylthiazole

71.47 g of 4-ethoxycarbonyl-5-iodothiazole was dissolved in 250 ml of DMF, 70 ml of triethylamine, 53.4 ml of ethynyltrimethylsilane, 960 mg of copper iodide, bis (triphenylphosphine) palladium ( II) 3.54 g of dichloride was added sequentially, and it stirred for 1.5 hours at 60 degreeC under argon atmosphere. The reaction solution was added to 100 ml of ethyl acetate and 500 ml of brine, and 1N hydrochloric acid was added to pH 3. The organic layer was separated and washed sequentially with 500 ml of sodium bicarbonate water and 500 ml of brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 3: 1) to 5- (2-trimethylsilyl). 53.66 g of tinyl) -4-ethoxycarbonylthiazole was obtained. This was dissolved in 250 ml of methanol, and under ice cooling, 3.1 g of potassium carbonate was added and stirred at the same temperature for 45 minutes. The reaction solution was added to 500 ml of ethyl acetate and 250 ml of brine, and the organic layer was separated and washed twice with 500 ml of brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 1) to give 5-ethynyl-4-meth. 29.91 g of oxycarbonylthiazole was obtained.

d) 5-ethynyl-4-hydroxymethylthiazole

To a solution of 25.05 g of 5-ethynyl-4-methoxycarbonylthiazole in 450 ml of toluene, 165 ml of 1.0 M hydrogenated diisobutylaluminum / toluene solution was added dropwise at -40 ° C under argon atmosphere. After stirring for 1 hour at the same temperature, the reaction solution was poured into saline, and 200 ml of 1N hydrochloric acid was added. After insoluble matter was removed by filtration by celite, the filtrate was extracted four times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was dissolved in 300 ml of ethanol and 150 ml of THF, and 2.2 g of sodium borohydride was added under an argon atmosphere under ice cooling, followed by stirring at room temperature for 1 hour. Saline was added to the reaction solution, 1N hydrochloric acid was added to pH 3, and the organic solvent was distilled off under reduced pressure. The remaining aqueous solution was extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (chloroform: ethyl acetate = 3: 1 to 1: 1), 19.25 g of 5-ethynyl-4-hydroxymethylthiazole was obtained.

e) 4-hydroxymethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

A solution of 2.73 g of 5-ethynyl-4-hydroxymethylthiazole in 65 ml of THF was ice-cooled under an argon atmosphere, and 6.5 g of triphenylmethanethiol and 440 mg of potassium-t-butoxide were added thereto. After stirring for 2 hours at room temperature, brine was added to the reaction solution, and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, 10 ml of ethyl acetate and 10 ml of hexane were added, and the precipitate was collected by filtration to obtain 7.26 g of the title compound.

Example 2 . 4- (2- Hydroxyethoxy ) methyl -5-((Z) -2- Tritylthioethene -1-yl) thiazole

a) 4-chloromethyl-5-((Z) -2-tritylthioethen-yl) thiazole

A 25 ml solution of 816 mg of 4-hydroxymethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 1-e) was cooled with ice, and triethyl under argon atmosphere. 0.301 ml of amine and 0.157 ml of thionyl chloride were added. After stirring for 20 minutes at the same temperature, brine was added to the reaction solution, and the pH was adjusted to 8 with sodium deuterium. The mixture was extracted twice with ethyl acetate, the organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 1: 1) to give 4-chloromethyl-5-((Z) -2-tritylthioethen-1-yl 512 mg of thiazole was obtained.

b) 4- (2-hydroxyethoxy) methyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

5.57 g of 4-chloromethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole are suspended in 100 ml of THF and 30 ml of ethylene glycol, 1.5 g of sodium hydride is added, and 37 at 50 ° C. Stirred for time. Saline was added to the reaction solution, extraction was performed twice with ethyl acetate, the organic layers were combined, washed twice with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain 4.87 g of the title compound.

Example  3. 4-N, N- Dimethyl carbamoyl -5-((Z) -2- Tritylthioethene -1-yl) thiazole

a) 4-methoxycarbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole and 4-methoxycarbonyl-5-((E) -2-tritylthio Eten-1-yl) thiazole

In the same manner as in Example 1-e), 4-methoxycarbonyl-5-((Z) -2-tritylthioethene-1- from 3.96 g of 5-ethynyl-4-methoxycarbonylthiazole 7.67 g of thiazole were obtained.

The residue obtained by concentrating the crystallized filtrate was recrystallized from chloroform-methanol-hexane to thereby form 4-methoxycarbonyl-5-((E) -2-tritylthioethen-1-yl) thiazole. 502 mg were obtained.

b) 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole

To a suspension of 7.31 g of 4-methoxycarbonyl-5-((Z) -2-tritylthioten-1-yl) thiazole was added 8.30 ml of 5N aqueous sodium hydroxide solution and stirred at 60 ° C for 1 hour. After cooling to room temperature, 8.50 ml of 5N hydrochloric acid, 100 ml of ethyl acetate, and 50 ml of water were added thereto, and the resultant was concentrated to 150 ml. 100 ml of hexane was added, and the precipitated solid was collected by filtration and washed with ethyl acetate-hexane (2: 1) to give 4-carboxy-5-((Z) -2-tritylthioethen-1-yl). 8.30 g of thiazole was obtained.

c) 4-N, N-dimethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

To a suspension of 7.34 g of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole in 100 ml of DMF, 1- [3- (dimethylamino) -propyl] -3-ethylcarr 3.91 g of bodyimide hydrochloride and 3.14 g of 1-hydroxybenzotriazole were added and stirred at room temperature for 30 minutes. 25.6 ml of 2M dimethylamine THF solution was added and stirred for 9 hours at the same temperature. 400 ml of ethyl acetate was added to the reaction solution, washed four times with 400 ml of brine, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was recrystallized from ethyl acetate hexane to give 5.73 g of the titled compound.

Example  4. 4- Hydroxymethyl -2-((Z) -2- Tritylthioethene -1-yl) thiazole

a) 4-ethoxycarbonyl-2-iodothiazole

A solution of 6.0 ml of t-butyl nitrite in 120 ml of acetonitrile was ice-cooled under an argon atmosphere, and 9.64 g of diiodomethane and 5.16 g of 2-amino-4-ethoxycarbonylthiazole were added thereto. After stirring for 1 hour at room temperature, brine was added and extracted twice with ethyl acetate. The organic layers were combined, washed twice with brine, dried over anhydrous magnesium sulfate, filtered, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 to 3: 1) to obtain 4 5.58 g of ethoxycarbonyl-2-iodothiazole was obtained.

b) 2-ethynyl-4-methoxycarbonylthiazole

6.39 g of 4-ethoxycarbonyl-2-iodothiazole was suspended in 60 ml of triethylamine, and under argon atmosphere, 253 mg of palladium acetate, 592 mg of triphenylphosphine and 6.37 ml of ethynyltrimethylsilane were added at 80 ° C. Stir for 2 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate and brine were added, and 1N hydrochloric acid was added to pH 3.0. Extract twice with ethyl acetate, wash with brine, dry the organic layer with anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to purify the residue by silica gel column chromatography (hexane: ethyl acetate = 5: 1). 3.97 g of 2- (2-trimethylsilylethynyl) -4-ethoxy carbonylthiazole were obtained. This was dissolved in 30 ml of methanol, and 220 mg of potassium carbonate was added under ice cooling, followed by stirring at room temperature for 30 minutes. Saline was added to the reaction solution, the mixture was extracted twice with ethyl acetate and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain 2.50 g of 2-ethynyl-4-methoxycarbonylthiazole.

c) 4-methoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

2.50 g of 2-ethynyl-4-methoxycarbonylthiazole-2 was dissolved in 70 ml of THF, and 4.96 g of triphenylmethylmercaptan and 336 mg of potassium-t-butoxide were added at -60 ° C under an argon atmosphere. . After stirring for 1 hour at the same temperature, an aqueous ammonium chloride solution was added to the reaction solution, and extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain a crude product containing the target substance. 3.88 g of 4-methoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole was obtained by adding ethyl acetate and hexane from the purified product and collecting the precipitate by filtration.

d) 4-hydroxymethyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

A solution of 3.48 g of 4-methoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole in 70 ml of dichloromethane was ice-cooled and, under argon atmosphere, 1.0 M hydrogenated diisobutyl 18.7 ml of aluminum / toluene solution was added dropwise. After stirring for 1 hour at the same temperature, water was added to the reaction solution, and the pH was adjusted to 2.5 with 1N hydrochloric acid. After insoluble matter was removed by filtration with celite, the filtrate was extracted twice with ethyl acetate, and the organic layers were combined and washed with brine. The residue obtained by drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 2.88 g of the title compound.

Example  5. 4- methyl -5-((Z) -2- Tritylthioethene -1-yl) thiazole

1.98 g of the title compound were obtained by the same method as Example 1-e) from 1.14 g of 4-methyl-5-ethynylthiazole.

Example  6. 4- Cabamo -5-((Z) -2- Tritylthiothene -1-yl) thiazole

a) 4-carbamoyl-5-ethynylthiazole

227 mg of bis (benzonitrile) palladium (II) dichloride, 239 mg of tri-tert-butylphosphine, 75 mg of copper iodide, trimethylsilylacetylene in 5.02 g of 4-carbamoyl-5-iodothiazole 5.55 ml and 4.14 ml of N, N-diisopropylamine were added and stirred at 40 ° C. for 1 day. Ethyl acetate and half saturated saline were added to the reaction solution, and the organic layer was dried over anhydrous magnesium sulfate after separation. From the residue removed by distillation of the solvent under reduced pressure, 20 ml of 30% aqueous ammonia and 10 ml of THF were added to the light brown solid obtained by recrystallization with dichloromethane-hexane. After stirring for 1 hour at room temperature, the solvent was concentrated and recrystallized from dichloromethane-ethyl acetate to give 474 mg of 4-carbamoyl-5-ethynylthiazole.

b) 4-carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

1.77 g of the title compound was obtained in the same manner as in Example 1-e) from 740 mg of 4-carbamoyl-5-ethynylthiazole.

Example  7. 4-N- Methylcarbamoyl -5-((Z) -2- Tritylthioethene -1-yl) thiazole

The title compound by the same method as Example 3-c) from 430 mg of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 1.0 ml of 2.0 M methylamine THF solution Obtained 397 mg.

Example  8. 4-N- Cyanomethyl -N- Methylcarbamoyl -5-((Z) -2- Tritylthioethene -1-yl) thiazole

The title compound was prepared in the same manner as in Example 3-c) from 1.10 g of 4-carboxy-5-((Z) -2-tritylthioethen-yl) thiazole and 0.392 ml of 2-methylaminoacetonitrile. 781 mg was obtained.

Example  9. 4-N- Cyanomethylcarbamoyl -5-((Z) -2- Tritylthioethene -1-yl) thiazole

The title compound by the same method as Example 3-c) from 1.41 g of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 609 mg of aminoacetonitrile (hydrochloride) Obtained 1.24 g.

Example  10. 4-N- (2- Cyanoethyl ) Cabamo -5-((Z) -2- Tritylthioethene -1-yl) thiazole

439 mg of the title compound was obtained by the same method as Example 3-c) from 430 mg of 4-carboxy-5-((Z) -2-tritylthioethen-yl) thiazole and 0.148 ml of 2-cyanoethanol. .

Example  11. 4- Cyanomethyl -5-((Z) -2- Tritylthioethene -1-yl) thiazole

A suspension of 350 mg of 4-chloromethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 2-a) in 7 ml of DMF was ice-cooled and sodium cyanide under argon atmosphere. 94 mg was added. After stirring at room temperature for 2.5 hours, brine was added to the reaction solution, the mixture was extracted twice with ethyl acetate, and the organic layers were combined and washed with brine. The residue obtained by drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 132 mg of the title compound.

Example  12. 4- (2- Methoxyethoxy ) methyl -5-((Z) -2- Tritylthioethene -1-yl) thiazole

436 mg of 4-chloromethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 2-a) in the same manner as in Example 2-b) and 2-methoxy 461 mg of the title compound was obtained from 7 ml of ethanol.

Example  13. 4- (3- Cyanoazetidine -1-yl) carbonyl-5-((Z) -2- Tritylthiothene -1-yl) thiazole

The title compound was prepared by the same method as Example 3-c) from 859 mg of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 237 mg of 3-cyanoatidine hydrochloride. 716 mg was obtained.

Example  14.4-N- (2- Hydroxyethyl ) Cabamo -5-((Z) -2- Tritylthioethene -1-yl) thiazole

871 mg of the title compound by the same method as Example 3-c) from 859 mg of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 0.24 ml of 2-aminoethanol Got it.

Example  15. 4-N- (3-hydroxypropan-1-yl) Cabamo -5-((Z) -2- Tritylthioethene -1-yl) thiazole

666 mg of the title compound by the same method as Example 3-c) from 644 mg of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 0.137 ml of 3-aminopropanol Got it.

Example  16. 4-N- (2- Hydroxyethyl ) -N- Methylcarbamoyl -5-((Z) -2- Tritylthioethene -1-yl) thiazole

From 644 mg of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 0.145 ml of 2- (methylamino) ethanol, the procedure was the same as in Example 3-c). 651 mg of compound were obtained.

Example  17. 4- ( Azetidine -1-yl) carbonyl-5-((Z) -2- Tritylthioethene -1-yl) thiazole

594 mg of the title compound was obtained by the same method as Example 3-c) from 644 mg of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 168 mg of azetidine hydrochloride.

Example  18. 4- (3- Hydroxyazetidine -1-yl) carbonyl-5-((Z) -2- Tritylthioethene -1-yl) thiazole

By the same method as Example 3-c) from 0.957 g of 4-carboxy-5-((Z) -2-tritylthioethen-1-yl) thiazole and 0.757 g of 3-hydroxyazetidine tartrate 0.742 g of the title compound were obtained.

Example  19. 4- (3-hydroxypropane-1- Iloxy ) methyl -5-((Z) -2- Tritylthioethene -1-yl) thiazole

665 mg and 1,3-4-chloromethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 2-a) in the same manner as in Example 2-b) 674 mg of the title compound were obtained from 3 ml of propanediol.

Example  20. 2-amino-4- Cabamo -5-((Z) -2- Tritylthioethene -1-yl) thiazole

a) 2-amino-4-ethoxycarbonyl-5-ethynylthiazole

1.40 g of 2-amino-4-ethoxycarbonyl-5-iodothiazole obtained in Example 1-a) was dissolved in 20 ml of N-methyl-2-pyrrolidinone, and in an argon atmosphere, tri-n- 1.63 ml of butylethynyl tin, 127 mg of tri (2-furyl) phosphines, 127 mg of tris (dibenzylideneacetone) dipalladium (0), and 1.27 g of zinc chloride were added and stirred at room temperature for 2.5 hours. Saline and ethyl acetate were added to the reaction solution, and the filtrate from which the insolubles were removed by filtration on celite was extracted twice with ethyl acetate, and the organic layers were combined and washed with brine. The residue obtained by drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 2-amino-4-ethoxycarbonyl-5-ethynyl. 597 mg of thiazole was obtained.

(b) 2-amino-4-ethoxycarbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

In the same manner as in Example 1-e), 2-amino-4-ethoxycarbonyl-5-((Z) -2-tri from 992 mg of 2-amino-4-ethoxycarbonyl-5-ethynylthiazole 1.93 g of methylthioethen-1-yl) thiazole were obtained.

c) 2-amino-4-carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

501 mg and 0.5 2-amino-4-ethoxycarbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole in the same manner as in Examples 3-b) and 3-c) 197 mg of the title compound were obtained from 8 ml of M ammonia / dioxane solution.

Example  21. 4- Hydroxymethyl -5-((E) -2- Tritylthioethene -1-yl) thiazole

From 480 mg of 4-methoxycarbonyl-5-((E) -2-tritylthioethen-1-yl) thiazole obtained in Example 3-a), by the same method as in Example 4-d). 330 mg of compounds were obtained.

Example  22. 2- Cabamo -5-((Z) -2- Tritylthioethene -1-yl) thiazole

a) 2-carbamoyl-5-ethynylthiazole

1.11 g of 2-carbamoyl-5-ethynylthiazole was obtained from 1.70 g of 2-carbamoyl-5-iodothiazole in the same manner as in Example 1-c).

b) 2-carbamoyl-5-((Z) -2-tritylthioethen-yl) thiazole

2.88 g of the title compound were obtained by the same method as Example 1-e) from 1.11 g of 2-carbamoyl-5-ethynylthiazole.

Example  23. 2-Amino-5-((Z) -2- Tritylthioethene -1-yl) thiazole

a) 2-amino-5-ethynylthiazole

To 30 ml of xylene suspension solution of 1.00 g of 2-amino-5-bromothiazole, 1.93 ml of tri-n-butylethynyl tin and 292 mg of bis (triphenylphosphine) palladium (II) dichloride were added, followed by 1 hour at 80 ° C. It stirred for 30 minutes at 100 degreeC, and 30 minutes at 120 degreeC. The reaction solution was concentrated, and the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain 1.70 mg of 2-amino-5-ethynylthiazole.

b) 2-amino-5-((Z) -2-tritylthioethen-1-yl) thiazole

616 mg of the title compound were obtained by the same method as Example 1-e) from 275 mg of 2-amino-5-ethynylthiazole.

Example  24. 2-N, N- Dimethyl carbamoyl -5-((Z) -2- Tritylthioethene -1-yl) thiazole

a) 2-N, N-dimethylcarbamoyl-5-ethynylthiazole

3.13 g of 2-N, N-dimethylcarbamoyl-5-ethynylthiazole was obtained in the same manner as in Example 4-b) from 5.69 g of 2-N, N-dimethylcarbamoyl-5-iodothiazole.

b) 2-N, N-dimethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole

5.27 g of the title compound were obtained by the same method as Example 1-e) from 2.80 g of 2-N, N-dimethylcarbamoyl-5-ethynylthiazole.

Example  25. 4- Cabamo -2-((Z) -2- Tritylthioethene -1-yl) thiazole

a) 2-bromo-4-carbamoylthiazole

To 1.51 g of 2-bromo-4-ethoxycarbonylthiazole, 10 ml of THF and 20 ml of 30% ammonia water were added and stirred at room temperature for 3 days. The reaction solution was concentrated to give 1.31 g of 2-bromo-4-carbamoylthiazole.

b) 4-carbamoyl-2-ethynylthiazole

209 mg of 4-carbamoyl-2-ethynylthiazole was obtained from 2.3 g of 2-bromo-4-carbamoylthiazole in substantially the same manner as in Example 4-b).

c) 4-carbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

417 mg of the title compound were obtained by the same method as Example 1-e) from 209 mg of 4-carbamoyl-2-ethynylthiazole.

Example  26. 4-N- (2- Hydroxyethyl ) Cabamo -2-((Z) -2- Tritylthioethene -1-yl) thiazole

443 mg of 4-methoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 4-c) was dissolved in 8 ml of THF, and 1.2 ml of 2-aminoethanol. Was added and stirred at 50 ° C. for 8 hours. THF was distilled off under reduced pressure, water and hydrochloric acid were added to pH 2, and extracted twice with dichloromethane.

Drying with anhydrous magnesium sulfate, filtration and concentration under reduced pressure, ethyl acetate was added to the residue, and the solid formed by filtration was collected to obtain 396 mg of the title compound.

Example  27. 4-N, N- Dimethyl carbamoyl -2-((Z) -2- Tritylthiothene -1-yl) thiazole

a) 4-carboxy-2-((Z) -2-tritylthioethen-1-yl) thiazole

In the same manner as in Example 3-b) from 2.65 g of 4-methoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 4-c), 2.33 g of 4-carboxy-2-((Z) -2-trityl thioethen-1-yl) thiazole were obtained.

b) 4-N, N-dimethylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

In the same manner as in Example 3-c), the title compound was obtained from 1.32 g of 4-carboxy-2-((Z) -2-tritylthioethen-1-yl) thiazole and 4.6 ml of 2M dimethyl amine / THF solution. 854 mg were obtained.

Example  28. 4-N- Methylcarbamoyl -2-((Z) -2- Tritylthioethene -1-yl) thiazole

0.136 ml of oxalyldichloride and 3 drops of DMF were added to 10 ml of a solution of 625 mg of 4-carboxy-2-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 27-a) in THF. Was added and stirred at room temperature for 15 minutes. 5 ml of 2M methylamine / THF solution was added at the same temperature, and after stirring for 30 minutes, 50 ml of ethyl acetate and 50 ml of saturated saline solution were added thereto. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethyl acetate-hexane to obtain 400 mg of the title compound.

Example  29. 4-N- Cyanomethylcarbamoyl -2-((Z) -2- Tritylthioethene -1-yl) thiazole

69 mg of the title compound was obtained by the same method as Example 3-c) from 85 mg of 4-carboxy-2-((Z) -2-tritylthioethen-yl) thiazole and 46 mg of amino acetonitrile sulfate.

Example  30. 4-N- Cyanomethyl -N- Methylcarbamoyl -2-((Z) -2- Tritylthioethene -1-yl) thiazole

The title compound was prepared in the same manner as in Example 3-c) from 85 mg of 4-carboxy-2-((Z) -2-tritylthioethen-1-yl) thiazole and 21 mg of N-methylaminoacetnitrile. 91 mg was obtained.

Example  31. 4- Cyanomethyl -2-((Z) -2- Tritylthioethene -1-yl) thiazole

2.614 g of the title compound were obtained by the same method as Example 2-a) and Example 11 from 2.801 g of 4-hydroxymethyl-2-((Z) -2-tritylthioethen-yl) thiazole .

Example  32. 4- (3- Hydroxyazetidine -1-yl) carbonyl-2-((Z) -2- Tritylthioethene -1-yl) thiazole

By the same method as Example 3-c) from 1.300 g of 4-carboxy-2-((Z) -2-tritylthioethen-1-yl) thiazole and 1.028 g of 3-hydroxyase thidine tartrate 1.169 g of the title compound were obtained.

Example  33. 4- (3- Cyanoazetidine -1-yl) carbonyl-2-((Z) -2- Tritylthioethene -1-yl) thiazole

From 0.356 g of 4-carboxy-2-((Z) -2-tritylthioethen-1-yl) thiazole and 0.149 g of 3-cyanoazetidine hydrochloride, titled by the same method as in Example 3-c) 0.271 g of compounds were obtained.

Example  34. 5- Hydroxymethyl -2-((Z) -2- Tritylthioethene -1-yl) thiazole

a) 5-ethoxycarbonyl-2-iodothiazole

In the same manner as in Example 4-a), 1.10 g of 5-ethoxycarbonyl-2-iodothiazole was obtained from 935 mg of 2-amino-5-ethoxycarbonylthiazole.

b) 5-ethoxycarbonyl-2-ethynylthiazole

In the same manner as in Example 20-a), 218 mg of 5-ethoxycarbonyl-2-ethynylthiazole was obtained from 997 mg of 5-ethoxycarbonyl-2-iodothiazole.

c) 5-ethoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

In the same manner as in Example 1-e), 5-ethoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl from 395 mg of 5-ethoxycarbonyl-2-ethynylthiazole 531 mg of thiazole was obtained.

d) 5-hydroxymethyl-2-((Z) -2-tritylthioten-1-yl) thiazole

10 ml of a solution of 257 mg of 5-ethoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole in THF was ice-cooled, and 1.0 M hydrogenated diisobutylaluminum / under argon atmosphere. 1.69 ml of toluene solution was dripped. After stirring at room temperature for 2 hours, water was added to the reaction solution and the pH was adjusted to 2.5 with 1N hydrochloric acid. After insoluble matter was removed by filtration with celite, the filtrate was extracted twice with ethyl acetate, and the organic layers were combined and washed with brine. Drying with anhydrous magnesium sulfate, filtration and concentration under reduced pressure gave 234 mg of the title compound.

Example  35.4.5- Dicabamo -2-((Z) -2- Tritylthioethene -1-yl) thiazole

a) 4,5-diethoxycarbonyl-2-iodothiazole

In the same manner as in Example 4-a), 662 mg of 4,5-diethoxycarbonyl-2-iodothiazole was obtained from 900 mg of 2-amino-4,5-diethoxycarbonylthiazole.

b) 4,5-diethoxycarbonyl-2-ethynylthiazole

4,5-diethoxycarbonyl-2-iodothiazole was added to 4,5-diethoxycarbonyl-2- in the same manner as in Example 4-b) except that ethanol was used instead of methanol. 539 mg of tinylthiazole were obtained.

c) 4,5-diethoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

4,5-diethoxycarbonyl-2-((Z) -2-tritylthiothene- from 389 mg of 4,5-diethoxycarbonyl-2-ethynylthiazole similarly to Example 1-e) 440 mg of 1-yl) thiazole were obtained.

d) 4,5-dicarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole

200 mg of 4,5-diethoxycarbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole as in Examples 3-b) and 3-c) and 0.5 M ammonia / 102 mg of the title compound were obtained from 3 ml of a dioxane solution.

Example  36. 4-((Z) -2- Tritylthioethene -1-yl) thiazole

a) 4-ethynylthiazole

9.83 g of bromomethyltriphenylphosphonium bromide was added to 100 ml of 7.27 g of potassium-t-butoxide in THF under ice-cooling, stirred at the same temperature for 10 minutes, and then 2.44 g of 4-formylthiazole was added. It was. After stirring at room temperature for 2 hours, 100 ml of ethyl acetate and 100 ml of half saturated saline were added, and the organic layer after separation was washed with half saturated saline. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (dichloromethane: hexane = 3: 2) to give 614 mg of 4-ethynylthiazole.

b) 4-((Z) -2-tritylthioethen-1-yl) thiazole

1.22 g of the title compound was obtained by the same method as Example 1-e) from 561 mg of 4-ethynylthiazole.

Example  37.2- Cabamo -4-((Z) -2- Tritylthioethene -1-yl) thiazole

a) 4-bromo-2-carbamoylthiazole

To 100 ml of a 2: 1 mixed solution of 4-bromo-2-carboxythiazole and THF-dichloromethane, 1.61 ml of oxalyldichloride was added and stirred at 60 ° C for 2 hours. 15 ml of 30% ammonia water was added to the reaction solution under ice-cooling, and stirred for 30 minutes at the same temperature. 50 ml each of ethyl acetate and half saturated saline was added, the organic layer was separated and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue obtained by silica gel column chromatography (chloroform: methanol = 40: 1). By purifying with 1.36 g of 4-bromo-2-carbamoylthiazole were obtained.

b) 2-carbamoyl-4-ethynylthiazole

694 mg of 2-carbamoyl-4-ethynylthiazole was obtained from 1.22 g of 4-bromo-2-carbamoylthiazole in the same manner as in Example 4-b).

c) 2-carbamoyl-4-((Z) -2-tritylthioethen-1-yl) thiazole

1.38 g of the title compound were obtained by the same method as Example 1-e) from 597 mg of 2-carbamoyl-4-ethynylthiazole.

Example  38. 5- Hydroxymethyl -4-((Z) -2- Tritylthioethene -1-yl) thiazole

a) 4-ethoxycarbonyl-5-hydroxymethylthiazole

7.13 g of 4,5-diethoxycarbonylthiazole was dissolved in 100 ml of ethanol, 2.20 g of sodium borohydride was added under argon atmosphere under ice cooling, followed by stirring at room temperature for 12 hours. Water was added to the reaction solution, 1N hydrochloric acid was added to pH 4.5, and then the organic solvent was distilled off under reduced pressure. The remaining aqueous solution was extracted five times with chloroform, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, ethyl acetate and hexane were added to the residue, and the resulting solid was collected by filtration to obtain 4-ethoxycarbonyl-5. 2.29 g of hydroxymethylthiazole were obtained.

b) 5-t-butyldimethylsilyloxymethyl-4-ethoxycarbonylthiazole

282 mg of 4-ethoxycarbonyl-5-hydroxymethylthiazole was dissolved in 5 ml of DMF, 123 mg of imidazole and 250 mg of t-butyldimethylsilyl chloride were added under an argon atmosphere under ice cooling, followed by stirring at room temperature for 1.5 hours. Saline was added to the reaction solution, extraction was performed twice with ethyl acetate, and the organic layers were combined and washed with brine. The residue obtained by drying with anhydrous magnesium sulfate, filtration, and concentrating under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 5-t-butyldimethylsilyloxymethyl-4-ethoxy. 374 mg of carbonylthiazole were obtained.

c) 5-t-butyldimethylsilyloxymethyl-4-formylthiazole

To a solution of 578 mg of 5-t-butyldimethylsilyloxymethyl-4-ethoxycarbonylthiazole in 10 ml of toluene, 2.4 ml of 1.0 M hydrogenated diisobutylaluminum / toluene solution was added dropwise at 60 ° C under argon atmosphere. After stirring at the same temperature for 2 hours, water and ethyl acetate were added to the reaction solution, and the pH was adjusted to 5.5 with 1N hydrochloric acid. After insoluble matter was removed by filtration by celite, the filtrate was extracted twice with ethyl acetate, the organic layers were combined and washed with brine. Drying with anhydrous magnesium sulfate, filtration and concentration under reduced pressure, the residue obtained is purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1 to ethyl acetate only) to give 5-t-butyldimethylsilyloxymethyl-4. -308 mg of formylthiazole was obtained.

d) 5-t-butyldimethylsilyloxymethyl-4-ethynylthiazole

In the same manner as in Example 36-a), 47 mg of 5-t-butyldimethylsilyloxymethyl-4-ethynylthiazole was obtained from 104 mg of 5-t-butyldimethylsilyloxymethyl-4-formylthiazole.

e) 5-t-butyldimethylsilyloxymethyl-4-((Z) -2-tritylthioethen-1-yl) thiazole

In the same manner as in Example 1-e), 5-t-butyldimethylsilyloxymethyl-4-((Z) -2-tritylthio from 165 mg of 5-t-butyldimethylsilyloxymethyl-4-ethynylthiazole 392 mg of ethen-1-yl) thiazole were obtained.

f) 5-hydroxymethyl-4-((Z) -2-tritylthioethen-1-yl) thiazole

Dissolve 392 mg of 5-t-butyldimethylsilyloxymethyl-4-((Z) -2-tritylthioethen-1-yl) thiazole in 10 ml of THF, add 0.7 ml of 5N hydrochloric acid and add 2 ml at room temperature. Stirred for time. Saline was added to the reaction solution, the pH was adjusted to 8 with sodium bicarbonate water, followed by extraction twice with ethyl acetate and washing with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, 5 ml of ethyl acetate and 5 ml of hexane were added, and the resulting solid was collected by filtration to obtain 180 mg of the title compound.

Example  39. 4- Ethoxycarbonyl -5- (2- Trimethylsilylethynyl Thiazole

a) 2-amino-5-bromo-4-ethoxycarbonylthiazole

In the same manner as in Example 1-a), 2-amino-4-ethoxycarbonylthiazole-43.05 g and 48.95 g of n-bromosuccinimide are 2-amino-5-bromo-4-ethoxy 46.27 g of carbonylthiazole were obtained.

b) 5-bromo-4-ethoxycarbonylthiazole

In the same manner as in Example 1-b), 31.31 g of 5-bromo-4-ethoxycarbonylthiazole was obtained from 48.65 g of 2-amino-5-bromo-4-ethoxycarbonylthiazole.

c) 4-ethoxycarbonyl-5- (2-trimethylsilylethynyl) thiazole

18.64 g of 5-bromo-4-ethoxycarbonylthiazole was dissolved in 80 ml of DMF, 22 ml of triethyl amine, 16.7 ml of ethynyltrimethylsilane, 960 mg of copper iodide, and bis (triphenylphosphine) palladium ( II) 1.11 g of dichloride was added sequentially, and it stirred at 90 degreeC under argon atmosphere for 1 hour. 80 ml of water, 160 ml of ethyl acetate and 160 ml of hexane were added to the reaction solution, and the mixture was washed sequentially with (saline + aqueous hydrochloric acid), sodium bicarbonate and brine. Activated carbon and anhydrous magnesium sulfate were added to the organic layer, and the resultant was filtered and concentrated under reduced pressure to obtain 16.45 g of the title compound.

Example  40. 4- Ethoxycarbonyl -5- Ethynylthiazole

1.45 g of 4-ethoxycarbonyl-5-iodothiazole was dissolved in 25 ml of N-methyl-2-pyrrolidinone, and under argon atmosphere, 1.78 ml of tri-n-butylethynyl tin and tri (2-furyl ) Phosphine 143 mg, tris (dibenzylideneacetone) dipalladium (0) 143 mg, zinc chloride 1.43 g were added, and it stirred at room temperature for 40 minutes. Saline and ethyl acetate were added to the reaction solution, and the filtrate from which the insolubles were removed by filtration on celite was extracted twice with ethyl acetate, and the organic layers were combined and washed with brine. The residue obtained by drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 750 mg of the title compound.

Example  41.Sodium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

a) silver salt of 4-hydroxymethyl-5-((Z) -2-mercaptoethen-1-yl) thiazole

To 50 ml of a solution of 2.5 g of 4-hydroxymethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 1 in THF, 0.511 ml of pyridine and 6.6 ml of 1N silver nitrate aqueous solution were added. It was added and stirred for 30 minutes at room temperature. The precipitated solid was collected by filtration, washed sequentially with 50 ml of acetone, 150 ml of 50% acetone-water, and 100 ml of acetone, and 4-hydroxymethyl-5-[(Z) -2-mercaptoethen-1-yl ] 2.15 g (78% purity) of the crude crystal of the silver salt of thiazole was obtained.

b) 4-nitrobenzyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl ) Ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

4-nitrobenzyl (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3 Crude crystal of silver salt of 4-hydroxymethyl-5-[(Z) -2-mercaptoethen-1-yl] thiazole in 10 ml of dry acetone solution of 599 mg of -carboxylate at 4 ° C. under argon atmosphere 283 mg was added followed by 303 mg sodium iodide. After stirring for 18 hours at the same temperature, 20 ml of ethyl acetate and 20 ml of half saturated saline were added, and the mixture was filtered through Celite and washed with ethyl acetate. The filtrate was separated and the organic layer was washed with half saturated saline. Dried over anhydrous magnesium sulfate, filtered, and ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give 4-nitrobenzyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- 298 mg of [[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate Got it.

c) sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene- 1-yl] thio] -1-methyl-1-carbafen-2-m-3 carboxylate

4-nitrobenzyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5- in THF 40ml Yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate 957 mg of 1/15 M sodium phosphate buffer (pH 6.8) in 40 ml solution of 10% Pd- 1.42 g of C (function, 53% water) were added, and the mixture was stirred for 1.5 hours under a hydrogen atmosphere. 10% palladium carbon was filtered, washed with water, and saturated sodium bicarbonate was added to the filtrate to pH 6.6. It was washed with 40 ml of ethyl acetate, the aqueous layer was concentrated to about 5 ml and purified by column chromatography (2% methanol-water) of Cosmsil 40C18-PREP to give the title compound (360 mg).

Example  42. (1R, 5S, 6S) -2-[[(Z) -2- [4- (2- Hydroxyethoxy ) Methylthiazole -5-day] ethen-1-yl] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

a) Silver salt of 4- (2-hydroxyethoxy) methyl-5-((Z) -2-mercaptoethen-1-yl) thiazole

4.83 g of 4- (2-hydroxyethoxy) methyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 2 was the same as in Example 41-a). 3.97 g (purity 85%) of silver salt of 4- (2-hydroxyethoxy) methyl-5-((Z) -2-mercaptoethen-1-yl) thiazole was obtained by the method.

b) 4-nitrobenzyl (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio ] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbafen-2-m-3-carboxylate

4-nitrobenzyl (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -1-methyl-6-((1R) -1-triethylsilyl-oxyethyl) -1-carba in dry acetonitrile To 60 ml of a solution of 6.20 g of phen-2-m-3-carboxylate, at room temperature under argon atmosphere, 4- (2-hydroxyethoxy) methyl-5-((Z) -2-mercaptoethene 3.97 g of crude crystals of the silver salt of -1-yl) thiazole were added, followed by 3.30 g of sodium iodide. After stirring for 18 hours at the same temperature, 200 ml of ethyl acetate and 200 ml of half saturated saline were added, and the mixture was filtered through Celite and washed with ethyl acetate. After separating the filtrate, the organic layer was washed with half saturated saline. Dried over anhydrous magnesium sulfate, filtered, and ethyl acetate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give 4-nitrobenzyl (1R, 5S, 6S) -2-[[(Z) -2- [4- (2- Hydroxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbafen-2-m 4.17 g of -3-carboxylate were obtained.

c) sodium (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -6 -((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

4-nitrobenzyl (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio]- 3.82 g of 1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbafen-2-m-3-carboxylate is dissolved in 170 ml of THF and 70 ml of water, and 1N hydrochloric acid 2.8 ml was added and stirred for 50 minutes at room temperature. After saturated sodium bicarbonate was added to the reaction solution to pH 3.0, 170 ml of 1/15 M sodium phosphate buffer (pH 6.8) and 10% Pd-C (function, 53% moisture) were added thereto, followed by stirring for 1.5 hours under a hydrogen atmosphere. It was. 10% Pd-C was filtered and washed with water, and saturated sodium bicarbonate was added to the filtrate to pH 7.0. Washed with 300 ml of ethyl acetate, concentrated the aqueous layer to about 20 ml, and purified by column chromatography (5% methanol-water) of Cosmosil 40C18-PREP to give 1.91 g of the title compound.

Example  43. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N- Dimethylcarbamoylthiazole -5 days) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

a) Silver salt of 4-N, N-dimethylcarbamoyl-5-((Z) -2-mercaptoethen-1-yl) thiazole

From 6.54 g of 4-N, N-dimethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 3, the same procedure as in Example 41-a) was repeated. 5.73 g (purity 80%) of crude crystals of the silver salt of -N, N-carbamoyl-5-((Z) -2-mercaptoethen-1-yl) thiazole were obtained.

b) 4-nitrobenzyl (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio]- 6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

4-nitrobenzyl (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen- in 100 ml of dry acetonitrile 4-N, N-dimethylcarbamoyl-5-((Z) -2-mercaptoethen-1-yl) to a solution of 8.51 g of 2-m-3-carboxylate at room temperature under argon atmosphere 5.73 g of crude crystal of the silver salt of thiazole was added, followed by 4.29 g of sodium iodide. After stirring at the same temperature for 13 hours, 300 ml of ethyl acetate and 200 ml of semisaturated saline were added, and the mixture was filtered through Celite and washed with ethyl acetate. After separating the filtrate, the organic layer was washed with half saturated saline. Dried over anhydrous magnesium sulfate, filtered, and ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica kell column chromatography (chloroform: methanol = 30: 1 to 20: 1) to thereby give 4-nitrobenzyl (1R, 5S, 6S) -2-[[(Z) -2- (4 -N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m 4.60 g of -3-carboxylate were obtained.

c) sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6- ( (1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

(1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R) 2.25 g of the title compound were obtained by the same method as Example 41-c) from 4.60 g of -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate.

Example  44. Sodium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4- Hydroxymethylthiazole -2 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

90.7 mg of the title compound was obtained by the same method as Example 42 from 370 mg of 4-hydroxymethyl-2-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 4.

Example  45. Sodium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl )-One- methyl -2-[[(Z) -2- (4-meth Tiltia Sol-5-day) Eten -1 day] Thio ]-One- Kabafen -2-m-3- Carboxylate

240 mg of the title compound were obtained by the same method as Example 43 from 1.95 g of 4-methyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 5.

Example  46. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4- Carbamoylthiazole -5 days) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

287 mg of the title compound was obtained by the same method as Example 42 from 2.03 g of 4-carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 6.

Example  47. Sodium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl )-One- methyl -2-[[(Z) -2- (4-N-meth Tilqaba Moly Tea Azole-5-day) Eten -1 day] Thio ]-One- Kabafen -2-m-3- Carboxylate

86 mg of the title compound was obtained by the same method as Example 42 from 394 mg of 4-N-methylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 7. .

Example  48. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N- Cyanomethyl -N- Methyl carbamoyl tea  Azole-5-day) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

From 1.24 g of 4-N-cyanomethyl-N-methylcarbamoyl-5-((Z) -2-tritylthioethen-l-yl) thiazole obtained in Example 8 in the same manner as in Example 43 This gave 487 mg of the title compound.

Example  49. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N- Cyanomethylcarbamoylthiazole -5 days) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

The title compound by the same method as in Example 43 from 1.24 g of 4-N-cyanomethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 9 487 mg was obtained.

Example  50. Sodium (1R, 5S, 6S) -2-[[(Z) -2- [4-N- (2- Cyanoethyl ) Kabamoyltia Sol-5-day] Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

4-N- (2-cyanoethyl) carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 10 by the same method as in Example 43 183 mg of the title compound were obtained.

Example  51. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4- Cyanomethylthiazole -5 days) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

117 mg of the title compound was obtained by the same method as Example 43 from 305 mg of 4-cyanomethyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 11.

Example  52. Sodium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- [4- (2- Methoxyethoxy ) Methylthiazole -5 days] Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

From 434 mg of 4- (2-methoxyethoxy) methyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 12 by the same method as in Example 43 159 mg of compound were obtained.

Example  53. Sodium (1R, 5S, 6S) -2-[[(Z) -2- [4- (3- Cyanoazetidine -1 day) Carbonylthiazole -5 days] Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3-car Fidelity Rate

Same as Example 43 from 694 mg of 4- (3-cyanoazetidin-1-yl) carbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 13. 63 mg of the title compound were obtained by the method.

Example  54. Sodium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) Carbamoylthiazole -5 days] Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

From 870 mg of 4-N- (2-hydroxyethyl) carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 14 by the same method as in Example 42 289 mg of the title compound were obtained.

Example  55. Sodium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- [4-N- (3-hydroxypropan-1-yl) Carbamoylthiazole -5 days] Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-M-3-ka Le Boxile T

Example 42 from 643 mg of 4-N- (3-hydroxypropan-1-yl) carbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 15. 284 mg of the title compound were obtained by the same method.

Example  56. Sodium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) -N- Methylcarbamoylthiazole -5 days] Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-M-3-ka Le Boxile T

Example 42 from 628 mg of 4-N- (2-hydroxyethyl) -N-methylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 16. 105 mg of the title compound were obtained by the same method.

Example  57. Sodium (1R, 5S, 6S) -2-[[(Z) -2- [4- ( Azetidine -1 day) Carbonylthiazole -5 days] Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

From 569 mg of 4- (azetidin-1-yl) carbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 17 by the same method as in Example 43. 230 mg of compounds of were obtained.

Example  58. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4- (3- Hydroxyazetidine -1 day) Carr Carbonylthiazol-5-yl) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-M-3-ka Le Boxile T

Example 42 from 0.742 g of 4- (3-hydroxyazetidin-1-yl) carbonyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 18. By the same method, 0.282 g of the title compound was obtained.

Example  59. Sodium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- [4- (3-hydroxypropane-1- Iloxy ) Methylthiazole -5 days] Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3-carboxylate

The same method as Example 42 from 903 mg of 4- (3-hydroxypropan-1-yloxy) methyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 19. 210 mg of the title compound were obtained.

Example  60. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (2-amino-4- Carbamoylthiazole -5-yl) ethen-1-yl] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

37 mg of the title compound was obtained by the same method as Example 42 from 182 mg of 2-amino-4-carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 20. Got it.

Example  61. Sodium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(E) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

36 mg of the title compound was obtained by the same method as Example 43 from 330 mg of 4-hydroxymethyl-5-((E) -2-tritylthioethen-1-yl) thiazole obtained in Example 21.

Example  62. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (2- Carbamoylthiazole -5 days) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

158 mg of the title compound was obtained in the same manner as in Example 42 from 2.88 g of 2-carbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 22.

Example  63. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (2- Aminothiazole -5 days) Eten -1-yl] thio] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

39 mg of the title compound was obtained by the same method as Example 42 from 596 mg of 2-amino-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 23.

Example  64. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (2-N, N- Dimethylcarbamoylthiazole -5 days) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

The title compound was obtained by the same method as Example 43 from 3.15 g of 2-N, N-dimethylcarbamoyl-5-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 24. 295 mg were obtained.

Example  65. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4- Carbamoylthiazole -2 days) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3 Carboxylate

24 mg of the title compound was obtained by the same method as Example 43 from 92 mg of 4-carbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 25.

Example  66. Sodium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- [4-N- (2-hydroxyethyl) Carbamoylthiazole -2 days] Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

From 371 mg of 4-N- (2-hydroxyethyl) carbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 26 by the same method as in Example 43 75 mg of the title compound were obtained.

Example  67. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N- Dimethylcarbamoylthiazole -2 days) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

From 854 mg of 4-N, N-dimethylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 27, the title compound was prepared by the same method as in Example 43. 273 mg were obtained.

Example  68. Sodium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl )-One- methyl -2-[[(Z) -2- (4-N-meth Tilqaba Moly Tea Azole-2-yl) Eten -1 day] Thio ]-One- Kabafen -2-m-3- Carboxylate

130 mg of the title compound were obtained by the same method as Example 43 from 745 mg of 4-N-methylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 28. .

Example  69. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N- Cyanomethylcarbamoylthiazole -2 days) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

The title compound was prepared in the same manner as in Example 43 from 68 mg of 4-N-cyanomethylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 29. 18mg was obtained.

Example  70. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N- Cyanomethyl -N- Methyl carbamoyl tea Azole-2-yl) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

By the same method as in Example 43 from 90 mg of 4-N-cyanomethyl-N-methylcarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 30 15 mg of the title compound were obtained.

Example  71. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4- Cyanomethylthiazole -2 days) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

739 mg of the title compound was obtained by the same method as Example 43 from 1.48 g of 4-cyanomethyl-2-((Z) -2-tritylthioten-1-yl) thiazole obtained in Example 31.

Example  72. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4- (3- Hydroxyazetidine -1 day) Carr Carbonylthiazol-2-yl) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-M-3-ka Le Boxile T

Example 43 from 1.28 g of 4- (3-hydroxyazetidin-1-yl) carbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 32. 208 mg of the title compound was obtained by the same method.

Example  73. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4- (3- Cyanoazetidine -1 day) Carbo Nylthiazol-2-yl) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3-carboxylate

Similar to Example 43 from 50 mg of 4- (3-cyanoazetidin-1-yl) carbonyl-2-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 33. 21 mg of the title compound were obtained by the method.

Example  74. Sodium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (5- Hydroxymethylthiazole -2 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

38 mg of the title compound was obtained by the same method as Example 43 from 234 mg of 5-hydroxymethyl-2-((Z) -2-tritylthioten-1-yl) thiazole obtained in Example 34.

Example  75. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4,5- Dicarbamoylthiazole -2 days) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

13 mg of the title compound from the 4,5-dicarbamoyl-2-((Z) -2-tritylthioethen-1-yl) thiazole 1 obtained in Example 35 by the same method as in Example 42 Got it.

Example  76. Sodium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl )-One- methyl -2-[[(Z) -2- (thiazol-4-yl) Eten -1 day] Thio ]-One- Kabafen -2-m-3- Carboxylate

354 mg of the title compound was obtained by the same method as Example 42 from 1.20 g of 4-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 36.

Example  77. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (2- Carbamoylthiazole -4- days) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

174 mg of the title compound was obtained by the same method as Example 42 from 1.38 g of 2-carbamoyl-4-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 37.

Example  78. Sodium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (5- Hydroxymethylthiazole -4- days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

9 mg of the title compound was obtained by the same method as Example 43 from 180 mg of 5-hydroxymethyl-4-((Z) -2-tritylthioethen-1-yl) thiazole obtained in Example 38.

Example  79. Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4- Acetoxymethylthiazole -5 days) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

a) 4-nitrobenzyl (1R, 5S, 6S) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl- 6-((1R) -1-triethylsilyloxyethyl) -1-carbafen-2-m-3-carboxylate

From 653 mg of crude crystals of silver salt of 4-hydroxymethyl-5-((Z) -2-mercaptoethenyl-yl) thiazole obtained in Example 41-a), in the same manner as in Example 42-b) 4-nitrobenzyl (1R, 5S, 6S) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-6- 582 mg of ((1R) -1-triethylsilyloxyethyl) -1-carbafen-2-m-3-carboxylate was obtained.

b) 4-nitrobenzyl (1R, 5S, 6S) -2-[[(Z) -2- (4-acetoxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl- 6-((1R) -1-triethylsilyloxyethyl) -1-carbafen-2-m-3-carboxylate

4-nitrobenzyl (1R, 5S, 6S) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl- in THF To 3 ml of a solution of 695 mg of 6-((1R) -1-triethylsilyloxyethyl) -1-carbafen-2-m-3-carboxylate, 37 mg of N, N-dimethylaminopyridine, 0.133 ml of pyridine, acetic acid 0.114 ml of anhydride was added, and it stirred at room temperature for 1.5 hours. Ethyl acetate was added to the reaction mixture, washed with brine, dried over anhydrous magnesium sulfate, and filtered. Filtrate added 5 g of silica gel to the filtrate, and the filtrate was concentrated under reduced pressure to give 4-nitrobenzyl (1R, 5S, 6S) -2-[[(Z) -2- (4-acetoxymethylthiazole-5 730 mg of -yl) ethen-1-yl] thio] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbafen-2-m-3-carboxylate was obtained.

c) sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-acetoxymethylthiazol-5-yl) ethen-1-yl] thio] -6-((1R)- 1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

As in Example 42-c), 4-nitrobenzyl (1R, 5S, 6S) -2-[[(Z) -2- (4-acetoxymethylthiazol-5-yl) ethen-1-yl 305 mg of the title compound were obtained from 725 mg of] thio] -1-methyl 6-((1R) -1-triethylsilyloxyethyl) -1-carbafen-2-m-3-carboxylate.

Example  80. Sodium (1R, 5S, 6S) -2-[[(Z) -2- [4- (2- Acetoxyethoxy ) Methylthiazole -5 days] Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate

a) 4-nitrobenzyl (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-acetoxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio ] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbafen-2-m-3-carboxylate

4-nitrobenzyl (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy) methylthiazol-5-yl] ethene obtained in Example 42-b) -1-yl] thio] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbafen-2-m-3-carboxylate, Example 79- In the same manner as b), 4-nitrobenzyl (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-acetoxyethoxy) methylthiazol-5-yl] ethene- 319 mg of 1-yl] thio] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbafen-2-m-3-carboxylate was obtained.

b) sodium (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-acetoxyethoxy) methylthiazol-5-yl] ethen-1-yl] thio] -6 -((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate

In the same manner as in Example 42-c), 4-nitrobenzyl (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-acetoxyethoxy) methylthiazol-5-yl ] Ethen-1-yl] thio] -1-methyl-6-((1R) -1-triethylsilyloxyethyl) -1-carbafen-2-m-3-carboxylate 135 mg of the title compound from 315 mg Got.

Example  81. 1- ( Cyclohexyloxycarbonyloxy Ethyl (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hi Doxy Ethoxy) Methylthiazole -5 days] Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl ) -1-methyl-1- Kabafen -2-m-3- Carboxylate  ( Diastereomer  compound)

Sodium (1R, 5S, 6S) -2-[[(Z) -2- [4- (2-hydroxyethoxy] ethen-1-yl] thio] -6- in 2 ml of N, N-dimethylacetamide To a solution of 51.8 mg of ((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate, 1- (cyclo) in hexane at -10 ° C under argon atmosphere 2 ml of a solution of 0.147 mg of hexyloxycarbonyloxy) ethyl iodide was added, after stirring for 1 hour at the same temperature, 2 ml of hexane was added to the reaction solution, and the upper and lower layers were separated. The mixture was extracted twice with ethyl acetate, and the combined organic layers were washed twice with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1). This gave 61.7 mg of the title compound.

Example  82. 1- ( Cyclohexyloxycarbonyloxy Ethyl (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-di Methylcarbamoyl Thiazol-5-yl) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylate  ( Diastereomer  mixture)

Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N, N-dimethylcarbamoylthiazol-5-yl) ethen-1-yl] thio]-obtained in Example 43- 969 mg of the title compound was obtained by the same method as Example 81 from 667 mg of 6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate.

Example  83. 1- ( Cyclohexyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -6-((1R) -1- He Doxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -2 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate  ( Diastereomer  mixture)

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-2 From 42.9 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 48 mg of 1- (cyclohexyloxycarbonyloxy) ethyl iodide 52.7 mg of the title compound were obtained.

Example  84. 1- ( Cyclohexyloxycarbonyloxy Ethyl (1R, 5S, 6S) -2-[[(Z) -2- (4-car Bamoiltia Sol-5-day) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kaba Pen-2-m-3- Carboxylate  ( Diastereomer  mixture)

Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R obtained in Example 46) 54 mg of the title compound was obtained by the same method as Example 81 from 70 mg of) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate.

Example  85. 1- ( Cyclohexyloxycarbonyloxy Ethyl (1R, 5S, 6S) -2-[[(Z) -2- (4-N-shi Anomethylcarbamoyl tea Azole-5-day) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl ) -1-methyl-1- Kabafen -2-m-3- Carboxylate  ( Diastereomer  mixture)

Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-N-cyanomethylcarbamoylthiazol-5-yl) ethen-1-yl] thio]-obtained in Example 49 From 60 mg of 6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate, 57 mg of the title compound was obtained by the same method as in Example 81.

Example  86. 1- ( Cyclohexyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -6-((1R) -1- He Doxyethyl) -2-[[(Z) -2- [4-N- (2- Hydroxyethyl ) Carbamoylthiazole -5 days] Eten -1 day] tea O] -1- methyl -One- Kabafen -2-m-3- Carboxylate  ( Diastereomer  mixture)

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxy From 69 mg of ethyl) carbamoylthiazol-5-yl] ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate, 85.6 mg of the title compound was obtained.

Example  87. Fibaroyloxymethyl  (1R, 5S, 6S) -2-[[(Z) -2- (2- Carbamoylthiazole -5 days) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -One- Kabafen -2-m-3- Carboxylic acid

Sodium (1R, 5S, 6S) -2-[[(Z) -2- (2-carbamoylthiazol-5-yl) ethen-1-yl] thio] -6-((1R obtained in Example 62) From 74 mg of) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate and 0.031 ml of iodomethyl pivalate, the title compound was prepared in the same manner as in Example 81. 78 mg was obtained.

Example  88. 1- ( Cyclohexyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- [4-N- (2- Hydroxyethyl ) Carbamoylthiazole -2 days] Eten -1-yl] thio] -1- methyl -One- Kabafen -2-m-3- Carboxylate  ( Diastereomer  mixture)

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- [4-N- (2-hydroxy Ethyl) carbamoylthiazol-2-yl] ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 38.5 mg and 1- (cyclohexyloxycarbonyl 45 mg of the title compound were obtained from 123 mg of oxy) ethyl iodide.

Example  89. 1- ( Cyclohexyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -6-((1R) -1- He Doxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Ka Waffen-2-M-3- Carboxylate  ( Diastereomer  mixture)

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 From 379 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate, 484 mg of the title compound were obtained.

Example  90. Acetoxymethyl  (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4-hi Doxymethylthia Sol-5-day) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl obtained in Example 41 146 mg of the title compound was obtained by the same method as Example 81 from 160 mg of) ethen-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 0.047 ml of bromomethyl acetate. .

Example  91. 1- ( Isopropyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -6-((1R) -1- He Doxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Ka Waffen-2-M-3- Carboxylate  ( Diastereomer  mixture)

Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl obtained in Example 41 From 133 mg of) ethen-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 110 mg of 1- (isopropyloxycarbonyloxy) ethyl iodide, it is similar to Example 81 137 mg of the title compound were obtained by the method.

Example  92. 1- ( Ethoxycarbonyloxy ) Ethyl (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate  ( Diastereomer  mixture)

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 From 145 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 148 mg of 1- (ethoxycarbonyloxy) ethyliodide 167 mg of compound was obtained.

Example  93. Fibaroyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4-hi Doxy Methylthiazol-5-yl) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl obtained in Example 41 From 104 mg of) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 0.049 ml of iodomethylpivalate, the title compound was obtained in the same manner as in Example 81. 93 mg was obtained.

Example  94. Cyclohexyloxycarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- Hydrock Cethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1- Ill] thio] -1-methyl-1-carbafen-2-m-3-carboxylate from 374 mg of cyclohexyloxycarbonyloxymethyl iodide, 336 mg of the title compound by the same method as in Example 81 372 mg were obtained.

Example  95. 1- ( Isobutyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -6-((1R) -1- Hide  Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kaba Pen-2-m-3- Carboxylate  ( Diastereomer  mixture)

Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl obtained in Example 41 Example 81 from 346 mg of) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 278 mg of 1- (isobutyloxycarbonyloxy) ethyl iodide, Example 81 334 mg of the title compound were obtained by the same method as the above.

Example  96. 1- ( Cyclohexyloxycarbonyloxy )-2- Methylpropane -1-yl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] tea O] -1- methyl -One- Kabafen -2-m-3- Carboxylate  ( Diastereomer  mixture)

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 -Yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 367 mg of 1- (cyclohexyloxycarbonyloxy) -2-methylpropane-1 From 300 mg of -day iodide, 84 mg of the title compound were obtained.

Example  97. Isobutyloxycarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- Hydroxy  Ethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 From 344 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 264 mg of isobutyloxycarbonyloxymethyl iodide, 294 mg of the title compound were Got it.

Example  98. Isopropyloxycarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- Hydrock Cethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 203 mg of the title compound were obtained from 348 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and isopropyloxycarbonyloxymethyl iodide. .

Example  99. Isobutyryloxymethyl  (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4-hi Doxy Methylthiazol-5-yl) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3 Carboxylate

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 360 mg of the title compound were obtained from 325 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbaphen-2-m-3-carboxylic acid carbonate and 220 mg of isobutyryloxymethyl iodide .

Example  100. (pentan-1-yl) Oxycarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- Hide Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1- Ill] thio] -1-methyl-1-carbaphen-2-m-3-carboxylate 150mg and (pentan-1-yl) oxycarbonyloxymethyl iodide from 162mg in the same manner as in Example 81 168 mg of the title compound were obtained.

Example l01 . (Butan-1-yl) Oxycarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- Hide Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 From 175 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 164 mg of (butan-1-yl) oxycarbonyloxymethyl iodide, 223 mg of the title compound were obtained.

Example  102. (1-ethylpropan-1-yl) Oxycarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1-hi De Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ] -1-methyl-1- Kabafen -2-m-3- Carboxylate

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 -Yl) ethen-1-yl] thio] -1-methyl-1-carbaphen-2-m-3-carboxylate and 149 mg and (1-ethylpropan-1-yl) oxycarbonyloxymethyl iodide From 120 mg, 154 mg of the title compound were obtained.

Example  103. Isopentyloxycarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 153 mg of the title compound were obtained from 150 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 120 mg of isopentyloxycarbonyloxymethyl iodide. Got it.

Example  104. (Propan-1-yl) Oxycarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- He Doxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 The title compound from 150 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 109 mg of (propan-1-yl) oxymethyl iodide 177 mg were obtained.

Example  105. 1- ( Cyclohexyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -2-[[(Z) -2- (4-a Cetoxymethylthia Sol-5-day) Eten -1 day] Thio ] -6-((1R) -1- Hydroxyethyl )-One- methyl -1-carbaphen-2-m-3- Carboxylate  ( Diastereomer  mixture)

Sodium (1R, 5S, 6S) -2-[[(Z) -2- (4-acetoxymethylthiazol-5-yl) ethen-1-yl] obtained in the same manner as in Example 81; Thio] -6-((1R) -1-hydroxyethyl) -1-methyl-1-carbafen-2-m-3-carboxylate 130 mg and 1- (cyclohexyloxycarbonyloxy) ethyl eye From 104 mg of ODID, 159 mg of the title compound were obtained.

Example  106. Ethoxycarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- On hydroxy Tyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-M-3-ka Le Boxile T

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 203 mg of the title compound were obtained from 214 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 146 mg of ethoxycarbonyloxymethyl iodide .

Example  107. Neopentyloxycarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 193 mg of the title compound was obtained from 160 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 129 mg of neopentyloxycarbonyloxymethyl iodide. Got it.

Example  108. Methoxycarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- On hydroxy Tyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-M-3-ka Le Boxile T

In the same manner as in Example 81, (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5- 148 mg of the title compound were obtained from 160 mg of il) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 103 mg of methoxycarbonyloxymethyl iodide.

Example  109. Cyclopentyloxycarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- Hide Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 167 mg of the title compound was obtained from 160 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 128 mg of cyclopentyloxycarbonyloxymethyl iodide. Got it.

Example  110.t- Butoxycarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- On hydroxy Tyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-M-3-ka Le Boxile T

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 From 176 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 135 mg of t-butoxycarbonyloxymethyl iodide, the title compound 214 mg were obtained.

Example  111. Phthalidyl  (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate  (D Asteromer  mixture)

The reaction was carried out in the same manner as in Example 81 except that the reaction was carried out at room temperature using only DMA as a solvent, and the reaction was performed in the same manner as in Example 81. 162 mg of 2--2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-em-3-carboxylate and 3-bromorph From 128 mg of talide, 122 mg of the title compound were obtained.

Example  112. 1- ( Methoxycarbonyloxy ) Ethyl (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate  ( Diastereomer  mixture)

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 From 163 mg of 1-()-ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 140 mg of 1- (methoxycarbonyloxy) ethyl iodide 145 mg of compound was obtained.

Example  113. 1- ( Cyclopentyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -1-carbaphen-2-m-3- Carboxylate  ( Diastereomer  mixture)

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 From 162 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 148 mg of 1- (cyclopentyloxycarbonyloxy) ethyl iodide, titled Compound 187 mg was obtained.

Example  114. ( Tetrahydropyran -4- days) Oxycarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1-hi De Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethyl -Thiazol-5-yl) Eten -1 day] Thio ] -1-methyl-1- Kabafen -2-m-3- Carboxylate

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 From 160 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 136 mg of (tetrahydropyran 4-yl) oxycarbonyloxymethyl iodide 194 mg of the title compound were obtained.

Example  115. 1- ( Neopentyloxycarbonyloxy ) Ethyl (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -1-carbaphen-2-m-3- Carboxylate  ( Diastereomer  mixture)

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 From 160 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 170 mg of 1- (neopentyloxycarbonyloxy) ethyl iodide, titled 100 mg of the compound was obtained.

Example  116. (Piperidin-1-yl) Carbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- Hide Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 From 160 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 130 mg of (piperidin-1-yl) carbonyloxymethyl iodide 192 mg of the title compound were obtained.

Example  117.Allyl (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl obtained in Example 41 1.00 g of) ethen-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 538 mg of allyl bromide and 415 mg of allyl iodide were prepared by the same method as in Example 81. 984 mg of compound were obtained.

Example  118. (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl )-One- methyl -2-[[(Z) -2- (4- (L-bal Ryloxyme Thi) thiazol-5-yl) Eten -1 day] Thio ]-One- Kabafen -2-m-3- Carboxylic acid

a) allyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (N-4-nitrobenzyloxy Carbonyl-L-valyloxymethyl) thiazol-5-yl) ethen-yl] thio] -1-carbafen-2-m-3-carboxylate

Allyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1- Il] thio] -1-methyl-1-carbafen-2-m-3-carboxylate was dissolved in 10 ml of N, N-dimethylacetamide to dissolve 281 mg of 4-dimethylaminopyridine, 1- [3- (dimethyl 441 mg of amino) propyl] -3-ethylcarbodiimide hydrochloride and 681 mg of N-4-nitrobenzyloxycarbonyl-L-valine were added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 50 ml of 20% saline and 50 ml of ethyl acetate, and the organic phase was dried over magnesium sulfate. Magnesium sulfate was removed by filtration and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate: n-hexane = 2: 1, then ethyl acetate: n-hexane = 5: 1) to give allyl (1R, 5S, 6S) -6- ( (1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (N-4-nitrobenzyloxycarbonyl-1-valyloxymethyl) thiazole-5- 517 mg of il) ethen-1-yl] thio] -1-carbafen-2-m-3-carboxylate was obtained.

b) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (N-4-nitrobenzyloxycarr Carbonyl-1-valyloxymethyl) thiazol-5-yl) ethen-1-yl] thio] -1-carbafen-2-m-3-carboxylic acid

Allyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (N-4-nitrobenzyloxycarbonyl Tetrahydrofuran of 500 mg of -L-valyloxy-methyl) thiazol-5-yl) ethen-1-yl] thio] -1-carbafen-2-m-3-carboxylate and 250 mg of dimedone It dissolved in 10 ml, 82 mg of tetrakistriphenylphosphine palladium was added, and it stirred for 30 minutes at room temperature under argon atmosphere. The reaction mixture was poured into 50 ml of 20% saline solution and 50 ml of ethyl acetate, and the pH was adjusted to 0.6 with 1N aqueous hydrochloric acid solution and the mixture was separated. The organic phase was dried over anhydrous magnesium sulfate, the solids were removed by filtration and the solvent was distilled off under reduced pressure. Purification by column chromatography of Sephadex LH-20 (dichloromethane: methanol = 1: 1) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl -2-[[(Z) -2- (4- (N-4-nitrobenzyloxycarbonyl-L-valyloxymethyl) thiazol-5-yl) ethen-1-yl] thio] -1-carba 317 mg of phen-2-m-3-carboxylic acid were obtained.

c) (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (L-valyloxymethyl) thiazole -5-yl) ethen-1-yl] thio] -1-carbafen-2-m-3-carboxylic acid

In the same manner as in Example 41-c), (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- From 150 mg of (N-4-nitrobenzyloxy-carbonyl-L-valyloxymethyl) thiazol-5-yl) ethen-1-yl] thio] -1-carbafen-2-m-3-carboxylic acid , (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -1-methyl-2-[[(Z) -2- (4- (L-valyloxymethyl) thiazole- 27 mg of 5-yl) ethen-1-yl] thio] -1-carbafen-2-m-3-carboxylic acid was obtained.

Example  119.1- (t- Butoxycarbonyloxy ) Ethyl (1R, 5S, 6S) -6-((1R) -1- Hydrock Cethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate ( Diastereomer  mixture)

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 From 160 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 162 mg of 1- (t-butoxycarbonyloxy) ethyl iodide, 89 mg of the title compound were obtained.

Example  120. 1- (t- Butoxycarbonyloxy ) Ethyl (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate  ( Diastereomer  mixture)

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 From 160 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 162 mg of 1- (t-butoxycarbonyloxy) ethyl iodide, 89 mg of the title compound were obtained.

Example  121. Ethyl (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 143 mg of the title compound were obtained from 265 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 0.063 ml of ethyl iodide.

Example  122. methyl -2-oxo-1,3- Dioxolene -4- days) methyl  (1R, 5S, 6S) -6-((1R) -1-hi Doxyrie Tyl) -2-[[(Z) -2- (4- Hydroxymethyl -Thiazol-5-yl) Eten -1 day] Thio ]-One- methyl -1-car bar Pen-2-m-3- Carboxylate

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 -Yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 160 mg (5-methyl-2-oxo-1,3-dioxolene-4- 156 mg of the title compound were obtained from 122 mg of i) methylbromide.

Example  123. Phenyloxycarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- On hydroxy Tyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-M-3-ka Le Boxile T

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 278 mg of the title compound were obtained from 226 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 243 mg of phenyloxycarbonyloxymethyl iodide. .

Example  124.N.N- Di (propan-1-yl) aminocarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1-hi De Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ] -1-methyl-1- Kabafen -2-m-3- Carboxylate

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 -Yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 159 mg and N, N-di (propan-1-yl) aminocarbonyloxymethyl eye From 135 mg of the oidide, 179 mg of the title compound were obtained.

Example  125. Cis -2,6-dimethylpiperidin-1-yl) Carbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-1-methyl-1- Kabafen -2-m-3- Carboxylate

a) (Cis-2,6-dimethylpiperidin-1-yl) carbonyloxymethyl chloride

To 46 ml of a solution of 9.11 ml of cis-2,6-dimethylpiperidine in toluene, 24 ml of a solution of 2.39 ml of chloromethyl chloroformate in toluene was added dropwise over 10 minutes under ice cooling, followed by stirring at room temperature for 16 hours. After 60 ml of 1N hydrochloric acid was added to the solution, the organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and 60 ml of 20% saline solution. Drying over anhydrous magnesium sulfate, filtration, and distilling off the solvent under reduced pressure gave 12.7 g of (cis-2,6-dimethylpiperidin-1-yl) carbonyloxymethyl chloride.

b) (Cis-2,6-dimethylpiperidin-1-yl) carbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z ) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

To 5 ml of a solution of 183 mg of (cis-2,6-dimethyl piperidin-1-yl) carbonyloxymethyl chloride in DMSO, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxyl The rate 300 mg was added, and it stirred at room temperature for 18 hours. 20 ml of ethyl acetate and 20 ml of 20% saline were added thereto, and the organic layer was washed twice with 20% saline. Dried over anhydrous magnesium sulfate, filtered, and ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 15: 1) to give 273 mg of the title compound.

Example  126.N.N-di- (butan-1-yl) Aminocarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1-hi De Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ] -1-methyl-1- Kabafen -2-m-3- Carboxylate

a) chloromethyl N, N-di-n-butylcarbamate

5.0 ml of chloromethyl chloroformate was added dropwise under ice cooling to 11.7 ml of triethylamine and 100 ml of N, N-di-n-butylamine in a cyclopentylmethylether solution, and stirred at room temperature for 13 hours. 100 ml of 2N hydrochloric acid was added and the solution was separated, and then the organic layer was washed with 100 ml of 5% aqueous sodium hydrogen carbonate solution and 100 ml of half saturated saline. Drying over anhydrous magnesium sulfate, filtration, and distilling off the solvent under reduced pressure gave 12.7 g of chloromethyl N, N-di-n-butylcarbamate.

b) N, N-di (butan-1-yl) aminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2 -(4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

In the same manner as in Example 125-b), 154 mg of chloromethyl N, N-di-n-butylcarbamate and sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2 233 mg-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate From 220 mg of the title compound were obtained.

Example  127. Hexane -1-yl (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4-hi Doxymethylthia Sol-5-day) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

In the same manner as in Example 81, sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5 162 mg of the title compound were obtained from 218 mg of -yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate and 0.095 ml of 1-hexane iodide.

Example  128.N- ( Hexane -1-yl) -N- Methylaminocarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1-hi De Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ] -1- Methyl-1- Kabafen -2-m-3- Carboxylate

a) chloromethyl N-n-hexyl-N-methylcarbamate

In the same manner as in Example 126-a), 4.64 g of chloromethyl N-n-hexyl-N-methylcarbamate was obtained from 3.17 g of N-n-hexyl-N-methylamine and 2.22 ml of chloromethyl chloroformate.

b) N- (hexane-1-yl) -N-methylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z)- 2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

In the same manner as in Example 125-b), 134 mg of chloromethyl Nn-hexyl-N-methylcarbamate and sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [ From 217 mg of [(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate, 206 mg of the title compound were obtained.

Example  129.N, N- Diisobutylaminocarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1-hi Doxyrie Tyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl 1-car bar Pen-2-m-3- Carboxylate

a) chloromethyl N, N-diisobutylcarbamate

In the same manner as in Example 126-a), 4.64 g of chloromethyl N, N-diisobutyl carbamate was obtained from 3.55 g of N, N-diisobutyl amine and 2.22 ml of chloromethyl chloroformate.

b) N, N-diisobutylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Roxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

In the same manner as in Example 125-b), 159 mg of chloromethyl N, N-diisobutylcarbamate and sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [ From 241 mg of [(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate, 242 mg of the title compound were obtained.

Example  130.N, N- Diisopropylaminocarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1-hi De Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ] -1- Methyl-1- Kabafen -2-m-3- Carboxylate

In the same manner as in Example 125-b), 133 mg of chloromethyl N, N-diisopropylcarbamate and sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [ From 231 mg of [(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate, 150 mg of the title compound were obtained.

Example  131.N- Cyclohexyl -N- Methylaminocarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1-hi De Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ] -1-methyl-1- Kabafen -2-m-3- Carboxylate

a) chloromethyl N-cyclohexyl-N-methylcarbamate

To 27 ml of a solution of 2.67 ml of chloromethyl chloroformate in toluene was added dropwise over 5 minutes while cooling with an ice bath, 4.39 ml of N-methylcyclo-N-hexyl amine and 5.44 ml of triethylamine in toluene over 5 minutes. It stirred at room temperature for 17 hours. After 60 ml of 1N hydrochloric acid was added to the solution, the organic layer was washed with 60 ml of 5% aqueous sodium hydrogen carbonate solution and 60 ml of 20% saline solution. It was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 5.76 g of chloromethyl N-cyclohexyl-N-methylcarbamate.

b) N-cyclohexyl-N-methylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

In the same manner as in Example 125-b), 122 mg of chloromethyl N-cyclohexyl-N-methylcarbamate and sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- From 200 mg of [[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate 165 mg of the title compound were obtained.

Example  132.N-pentane-1- Monoaminocarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1- He Doxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

a) chloromethyl N-pentan-1-ylcarbamate

To 24 ml of a 2.39 ml chloromethyl chloroformate solution in toluene, 3.84 ml of n-pentylamine and 38 ml of a solution of 5.02 ml of triethylamine in toluene were added dropwise over 15 minutes while cooling with an ice bath, followed by stirring at room temperature for 15 hours. . After 60 ml of 1N hydrochloric acid was added to the solution, the organic layer was washed with 60 ml of 5% aqueous sodium hydrogen carbonate solution and 60 ml of 20% saline solution. After drying over anhydrous magnesium sulfate, filtration, and distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1) to give chloromethyl N-pentan-1-ylcarbamate 3.31 g was obtained.

b) N-pentan-1-ylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Roxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

In the same manner as in Example 125-b), 160 mg of chloromethyl N-pentan-1-yl-N-methylcarbamate and sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxyl From 300 mg of rate, 125 mg of the title compound were obtained.

Example  133.N- Cyclohexyl -N- Ethylaminocarbonyloxymethyl   (1R, 5S, 6S) -6-((1R) -1-hi De Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ] -1-methyl-1- Kabafen -2-m-3- Carboxylate

a) chloromethyl N-cyclohexyl-N-ethylcarbamate

6.44 g of chloromethyl N-cyclohexyl-N-ethylcarbamate were obtained from 10 ml of N-ethyl-N-cyclohexylamine and 2.68 ml of chloromethyl chloroformate in the same manner as in Example 125-a).

b) N-cyclohexyl-N-ethylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

In the same manner as in Example 125-b), 190 mg of chloromethyl N-cyclohexyl-N-ethylcarbamate and sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- From 300 mg of [[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate 285 mg of the title compound were obtained.

Example  134.N-isobutyl-N- Isopropylaminocarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ] -1-methyl-1- Kabafen -2-m-3- Carboxylate

a) chloromethyl N-isobutyl-N-isopropylcarbamate

To 870 mg of N-isobutylisopropylamine, 9 ml of toluene, 1.42 ml of N, N-diisopropylethyl amine, and 0.56 ml of chloromethyl chloroformate were sequentially added, followed by stirring at room temperature for 16 hours. 15 ml of 1N hydrochloric acid was added thereto, followed by separating an organic layer. Drying with anhydrous magnesium sulfate, filtration, distilling off the solvent under reduced pressure gave 1.23 g of chloromethyl N-isobutyl-N-isopropylcarbamate.

b) N-isobutyl-N-isopropylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4 -Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

In the same manner as in Example 125-b), 177 mg of chloromethyl N-isobutyl-N-isopropylcarbamate and sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2 300 mg of [[((Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate From 279 mg of the title compound were obtained.

Example  135.N-t-butyl-N- Ethylaminocarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1-hi Doxyrie Tyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl 1-car bar Pen-2-m-3- Carboxylate

a) chloromethyl N-t-butyl-N-ethylcarbamate

In the same manner as in Example 125-a), 5.54 g of chloromethyl N-t-butyl-N-ethylcarbamate was obtained from 9.15 ml of N-t-butylethylamine and 2.67 ml of chloromethyl chloroformate.

b) Nt-butyl-N-ethylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy Roxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

In the same manner as in Example 125-b), 180 mg of chloromethyl Nt-butyl-N-ethylcarbamate and sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [ From 300 mg of [(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate, 273 mg of the title compound were obtained.

Example  136. 1- (N, N- Diisopropylaminocarbonyloxy ) Ethyl (1R, 5S, 6S) -6-((1R) -1-hi De Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ] -1- Methyl-1- Kabafen -2-m-3- Carboxylate  ( Diastereomer  mixture)

a) 1-chloroethyl N, N-diisopropylcarbamate

In the same manner as in Example 125-a), 10.2 g of 1-chloroethyl N, N-diisopropylcarbamate was obtained from 15.4 ml of N, N-diisopropyl amine and 5.40 ml of 1-chloroethyl chloroformate.

b) 1- (N, N-diisopropylaminocarbonyloxy) ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

In the same manner as in Example 125-b), 247 mg of 1-chloroethyl N, N-diisopropylcarbamate and sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2 400 mg of [[((Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate From 92 mg of the title compound were obtained.

Example  137. 1-[(cis-2,6-dimethylpiperidin-1-yl) Carbonyloxy ] Ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] tea O] -1- methyl -One- Kabafen -2-m-3- Carboxylate  ( Diastereomer  mixture)

a) 1-[(Cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl chloride

In the same manner as in Example 125-a), 8.45 g of cis-2,6-dimethylpiperidine and 3.66 ml of 1-chloroethyl chloroformate gave 1-[(cis-2,6-dimethylpiperidine- 6.01 g of 1-yl) carbonyloxy] ethyl chloride was obtained.

b) 1-[(Cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- [[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m 3-carboxylate (diastereo Flour mixture)

In the same manner as in Example 125-b), 283 mg of 1-[(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy] ethyl chloride and sodium (1R, 5S, 6S) -6- ( (1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carba From 404 mg of phen-2-m-3-carboxylate, 98 mg of the title compound were obtained.

Example  138.N-ethyl-N- Isoamylaminocarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1-hi De Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethyl -Thiazol-5-yl) Eten -1 day] Thio ] -1-methyl-1- Kabafen -2-m-3- Carboxylate

a) chloromethyl N-ethyl-N-isoamylcarbamate

In the same manner as in Example 125-a), 207 mg of chloromethyl N-ethyl-N-isoamylcarbamate was obtained from 228 mg of N-ethyl-N-isoamylamine and 0.089 ml of chloromethyl chloroformate.

b) N-ethyl-N-isoamylaminocarbonyloxymethyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate

In the same manner as in Example 125-b), 202 mg of chloromethyl N-ethyl-N-isoamylcarbamate and sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2- From 328 mg [[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate 213 mg of the title compound were obtained.

Example  139. (5- Bromothiazole -4-yl) methanol

29.4 g of calcium chloride dihydrate, 11.80 g of ethyl-5-bromothiazole-4-carboxylate, and 30 ml of THF were sequentially added to 60 ml of water, followed by stirring. After adjusting the temperature of the reaction liquid to 0-2 degreeC, 3.78 g of sodium borohydride was thrown in at 5 degrees C or less of reaction liquid temperature. After stirring for 2 hours at the temperature of the reaction liquid 2-7 degreeC, 22 ml of acetone and 20 ml of 5N hydrochloric acid were sequentially added at the temperature of 7 degrees C or less of reaction liquid. After 30 minutes of stirring at the same temperature, the mixture was adjusted to pH 5 with 5N aqueous sodium hydroxide solution. The reaction mixture was extracted with 120 ml of ethyl acetate, and the separated aqueous layer was extracted with 120 ml of ethyl acetate to combine the organic layers. The organic layer was washed sequentially with 60 ml of 5% sodium bicarbonate, 30 ml of 5% sodium bicarbonate, and 30 ml of 20% brine, the aqueous layers were combined, extracted with 120 ml of ethyl acetate, and the organic layers were combined. 7.64 g of (5-bromothiazol-4-yl) methanol was obtained by drying an organic layer with anhydrous magnesium sulfate, filtration, distilling a solvent off and removing the obtained solid.

Example  140. [5- [2- ( Trimethylsilyl ) Ethynyl ] -Thiazol-4-yl] -methanol

To 25 ml of DMF, 6.15 g of (5-bromothiazol-4-yl) methanol, 8.9 ml of triethylamine, 61 mg of copper (I) iodide, 5.4 ml of trimethylsilylacetylene, bis (triphenylphosphine) palladium (II) dichloride 223 mg were added sequentially, the mixture was stirred and the air of the system was replaced with argon. The reaction mixture was heated and stirred at 90 ° C. for 90 minutes and then radiated. 74 ml of toluene and 25 ml of water were added to the reaction mixture, and the aqueous layer was separated. 25 ml of water was added to the organic layer, the pH was adjusted to 2 in 5N hydrochloric acid, and the aqueous layer was separated. The organic layer was washed sequentially with 25 ml of 5% sodium bicarbonate and 25 ml of 10% saline, and treated with 1.4 g of activated carbon and anhydrous magnesium sulfate. 5.35 g of [5- [2- (trimethylsilyl) ethynyl] thiazol-4-yl] methanol was obtained by distilling off the solvent and separating the obtained solid.

Example  141. 5- Ethynyl -4- Hydroxymethylthiazole

39 mg of potassium carbonate was added to a solution of 6.02 g of [5- [2- (trimethylsilyl) ethynyl] thiazol-4-yl] methanol in 12 ml of methanol, and stirred at room temperature for 10 minutes. 6 ml of 10% aqueous citric acid solution was added thereto, stirred for 30 minutes, and the reaction mixture was extracted with 90 ml of ethyl acetate. The organic layer was washed sequentially with 12 ml of 5% sodium bicarbonate and 12 ml of 20% brine, and treated with 0.8 g of activated carbon and anhydrous magnesium sulfate. 15 ml of toluene was added to the obtained organic layer, and the precipitated solid was collected by filtration to obtain 3.11 g of 5-ethynyl-4-hydroxymethylthiazole.

Example  142.N, N- Diisopropylaminocarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1-hi De Oxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ] -1-methyl-1- Kabafen -2-m-3- Carboxylate

Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole- in N, N-dimethylacetamide To 50 ml of a solution of 4.89 g of 5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate, chloromethyl N, N-diisopropylcarbamate 2.81 g and 2.76 g of triethyl benzyl ammonium chloride were added, and it stirred at 30 degreeC for 5 hours. After the reaction solution was washed twice with 180 ml of heptane, 125 ml of ethyl acetate and 125 ml of 20% saline solution were added thereto. After separation, the organic layer was washed three times with 125 ml of 10% saline. After drying over anhydrous magnesium sulfate and filtration, ethyl acetate was distilled off under reduced pressure to obtain 6.01 g of the title compound.

Example  143. Sodium (5R, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- Kabafen -2-m-3- Carboxylate

a) 4-nitrobenzyl (5R, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethene -1-yl] thio] -1-carbafen-2-m-3-carboxylate

4-nitrobenzyl (1R, 5R, 6S) -2- (diphenylphosphoryloxy) -6-((1R) -1-hydroxyethyl) -1-methyl-1-carba of Example 41-b) 4-nitrobenzyl (5R, 6S) -2- (diphenylphosphoryloxy) -6-((1R) -1-hydroxyethyl) -1 instead of using phen-2-m-3-carboxylate 4-Nitrobenzyl (5R, 6S) -6-((1R) -1-hydroxyethyl) -2- in approximately the same manner except that 4.13 g of carbafen-2-m-3-carboxylate was used. 2.76 g of [[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-carbafen-2-m-3-carboxylate was obtained.

b) Sodium (5R, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1- Yl] thio] -1-carbafen-2-m-3-carboxylate

In the same manner as in Example 41-c), 4-nitrobenzyl (5R, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxy From 2.10 g of methylthiazol-5-yl) ethen-1-yl] thio] -1-carbafen-2-m-3-carboxylate, 259 mg of the title compound were obtained.

Example  144.N, N- Diisopropylaminocarbonyloxymethyl  (5R, 6S) -6-((1R) -1- He Doxyethyl) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- Kabafen -2-m-3- Carboxylate

Sodium (5R, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazole-5- in N, N-dimethylacetamide To 2 ml of a solution of 100 mg of 1) ethen-1-yl] thio] -1-carbafen-2-m-3-carboxylate, 54 mg of chloromethyl N, N-diisopropylcarbamate, n-tetrabutylammonium bromide 75 mg was added, and it stirred at 30 degreeC for 3 hours and 30 minutes. 10 ml of ethyl acetate and half saturated saline were added to the reaction solution, and the organic layer was washed three times with 10 ml of half saturated saline. Dried over anhydrous magnesium sulfate, filtered, and ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate: methanol = 15: 1) to obtain 108 mg of the title compound.

Example  145. (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

Sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethylthiazol-5-yl) ethen-1- 7.10 ml of 1N hydrochloric acid was added to 120 ml of an aqueous solution of 2.73 g of yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate at room temperature and stirred for 3 minutes. Extracted twice with 150 ml of ethyl acetate, dried over anhydrous magnesium sulfate, and filtered, the ethyl acetate was distilled off under reduced pressure to 50 ml. 200 ml of hexane was added and the precipitated solid was collected by filtration to obtain 1.63 g of the title compound.

Example  146. Potassium (1R, 5S, 6S) -6-((1R) -1- Hydroxyethyl ) -2-[[(Z) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ]-One- methyl -One- Kabafen -2-m-3- Carboxylate

4-nitrobenzyl (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[(Z) -2- (4-hydroxymethyl in 2.5 ml of water and 7.5 ml of THF Thiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbaphen-2-m-3-carboxylate 10% Pd-C catalyst (function, moisture 53) %) 500 mg were added, and it stirred for 3 hours, maintaining 30 degreeC-35 degreeC under hydrogen atmosphere. The catalyst was filtered off, and 1.7 ml of 1 M aqueous potassium hydrogen carbonate solution and 0.061 ml of 2-ethylhexanoate were added to the filtrate. 80 ml of ethyl acetate was washed, and the aqueous layer was concentrated to about 10 ml. The precipitated insolubles were removed by filtration, and then concentrated to about 8 ml again, 60 ml of acetone was added, and the mixture was stirred for 1 hour under ice cooling. The precipitated solid was collected by filtration to give 432 mg of the title compound.

Example  147.N.N- Diisopropylaminocarbonyloxymethyl  (1R, 5S, 6S) -6-((1R) -1-hi De Oxyethyl) -2-[[(E) -2- (4- Hydroxymethylthiazole -5 days) Eten -1 day] Thio ] -1-methyl-1- Kabafen -2-m-3- Carboxylate

In the same manner as in Example 144, 50.4 mg of chloromethyl N, N-diisopropylcarbamate and sodium (1R, 5S, 6S) -6-((1R) -1-hydroxyethyl) -2-[[( E) -2- (4-hydroxymethylthiazol-5-yl) ethen-1-yl] thio] -1-methyl-1-carbafen-2-m-3-carboxylate from 87.8 mg, titled Obtained 90.9 mg of the compound.

The compounds prepared in Examples are shown in Tables 1-10.

In the table, Me is methyl group, Et is ethyl group, iPr is isopropyl group, nPr is n-propyl group, nBu is n-butyl group, tBu is tert-butyl group, Tr is trityl (triphenylmethyl) group, TMS Represents a trimethylsilyl group, and E / Z represents the stereo of a thioethenyl site | part.

TABLE 1

TABLE 2

TABLE 3

TABLE 4

TABLE 5

TABLE 6

TABLE 7

TABLE 8

TABLE 9

TABLE 10

[ Test Example  1] antimicrobial activity

Hereinafter, the minimum growth inhibitory concentrations (MIC, μg / ml) of various pathogens of representative compounds in the novel carbapenem derivatives of the present invention were determined by CHEMOTHERAPY, vol. It measured according to the method of description of 16, No.1, 99, 1968, and the result is shown in Table 11. The measurement medium is Sensitivity Disk agar-N + 5% Horse blood, and the inoculum amount was 10 ⁶ CFU / ml.

The comparative material was set to IPM (imipenem).

TABLE 11

According to the present invention there is provided a 2-ethenylthio based carbapenem derivative of formula (I) or a pharmaceutically acceptable salt thereof. The compound according to the present invention has a strong antibacterial activity against pneumococcal bacteria including penicillin-resistant pneumococci (PRSP), influenza bacteria including β-lactase aerobic influenzae bacteria (BLNAR), and bacteriostatic bacteria, and a wide range. Has an antibacterial spectrum.

Claims (22)

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

[In the meal, R ¹ represents a hydrogen atom or a methyl group, R ² and R ³ are the same or different, respectively,   Hydrogen atom,   Halogen atom,   Amino Group,   Substituted amino groups,   Lower alkyl group,   Substituted lower alkyl group,   Carbamoyl,   Substituted aminocarbonyl groups,   Lower alkoxycarbonyl group,   Substituted lower alkoxycarbonyl groups,   Heterocyclic carbonyl group, or   Substituted heterocyclic carbonyl group, R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo. The compound of claim 1, wherein R ² and R ³ are the same as or different from each other,   Hydrogen atom,   Halogen atom,   Amino Group,   Substituted amino groups,   Lower alkyl group,   Hydroxy lower alkyl group,   Cyano lower alkyl group,   Lower alkoxy-lower alkyl groups,   Substituted lower alkoxy-lower alkyl group,   Lower alkoxy-lower alkoxy-lower alkyl groups,   Substituted lower alkoxy-lower alkoxy-lower alkyl group,   Acyloxy lower alkyl group,   Substituted acyloxy lower alkyl groups,   Carbamoyl,   Mono-lower alkylcarbamoyl groups,   Substituted mono-lower alkylcarbamoyl groups,   Di-lower alkylcarbamoyl groups,   Substituted di-lower alkylcarbamoyl groups,   Lower alkoxycarbonyl group,   Azetidinylcarbonyl group, or,  A compound, or a pharmaceutically acceptable salt thereof, characterized in that it represents a substituted azetidinylcarbonyl group. The compound of claim 1, wherein R ² and R ³ are the same as or different from each other,   Hydrogen atom,   Halogen atom,   Amino Group,   Methyl group,   Cyanomethyl Group,   Hydroxymethyl group,   Acetoxymethyl group,   (2-hydroxyethoxy) methyl group,   (3-hydroxypropyloxy) methyl group,   (2-methoxyethoxy) methyl group,   (2-acetoxyethoxy) methyl group,   L-valyloxymethyl group,   Carbamoyl,   N-methyl carbamoyl group,   N-cyanomethylcarbamoyl group,   N- (2-cyanoethyl) carbamoyl group,   N- (2-hydroxyethyl) carbamoyl group,   N- (3-hydroxypropyl) carbamoyl group,   N, N-dimethylcarbamoyl group,   N- (2-hydroxyethyl) -N-methylcarbamoyl group,   N-cyanomethyl-N-methylcarbamoyl group,   Methoxycarbonyl group,   Ethoxycarbonyl group,   (Azetidin-1-yl) carbonyl group,   (3-cyanoazetidin-1-yl) carbonyl group, or  A compound, or a pharmaceutically acceptable salt thereof, characterized in that it represents a (3-hydroxyazetidin-1-yl) carbonyl group. A compound of formula (II), or a pharmaceutically acceptable salt thereof:

[In the meal, R ¹ represents a hydrogen atom or a methyl group, Ring A is   4-hydroxymethylthiazole,   5-hydroxymethylthiazole,   4- (2-hydroxyethoxy) methylthiazole,   4-N, N-dimethylcarbamoylthiazole,   2-N, N-dimethylcarbamoylthiazole,   4-methylthiazole,   4-carbamoylthiazole,   2-carbamoylthiazole,   4-N-methylcarbamoylthiazole,   4-N-cyanomethyl-N-methylcarbamoylthiazole,   4-N-cyanomethylcarbamoylthiazole,   4-N- (2-cyanoethyl) carbamoylthiazole,   4-cyanomethylthiazole,   4- (2-methoxyethoxy) methylthiazole,   4- (3-cyanoazetidin-1-yl) carbonylthiazole,   4-N- (2-hydroxyethyl) carbamoylthiazole,   4-N- (3-hydroxypropan-1-yl) carbamoylthiazole,   4-N- (2-hydroxyethyl) -N-methylcarbamoylthiazole,   4- (azetidin-1-yl) carbonylthiazole,   4- (3-hydroxyazetidin-1-yl) carbonylthiazole,   4- (3-hydroxypropan-1-yloxy) methylthiazole,   2-amino-4-carbamoylthiazole,   2-aminothiazole,   4,5-dicarbamoylthiazole,   4-acetoxymethylthiazole,   4- (2-acetoxyethoxy) methylthiazole,   4- (L-valyloxymethyl) thiazole,   4-methoxycarbonylthiazole,   4-ethoxycarbonylthiazole,   2-amino-4-methoxycarbonylthiazole, or   2-amino-4-ethoxycarbonylthiazole, R ⁴ represents a hydrogen atom or a group that can be hydrolyzed in vivo. The compound of any one of claims 1-4, wherein R ¹ is a methyl group, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 5, wherein R ⁴ is   Hydrogen atom,   Lower alkyl group,   Lower alkenyl,   Lower alkylcarbonyloxy-lower alkyl group,   Lower cycloalkylcarbonyloxy-lower alkyl groups,   Lower cycloalkylmethylcarbonyloxy-lower alkyl group,   Lower alkenylcarbonyloxy-lower alkyl group,   Arylcarbonyloxy-lower alkyl group,   Tetrahydrofuranylcarbonyloxy methyl group,   Lower alkoxy-lower alkyl groups,   Lower alkoxy-lower alkoxy-lower alkyl groups,   Arylmethyloxy-lower alkyl group,   Aryl methyloxy-lower alkoxy-lower alkyl group,   Lower alkoxycarbonyloxy-lower alkyl group,   Lower alkoxycarbonyloxy-lower alkoxy group,   Lower cycloalkoxycarbonyloxy-lower alkyl group,   Lower cycloalkylmethoxycarbonyloxy-lower alkyl group,   Aryloxycarbonyloxy-lower alkyl group,   3-phthalidyl group optionally having a substituent on the aromatic ring,   Optionally a 2- (3-phthalidylidene) ethyl group on the aromatic ring,   2-oxotetrahydrofuran-5-yl group,   4-tetrahydropyranyloxycarbonyloxy lower alkyl group,   Mono-lower alkylaminocarbonyloxy lower alkyl group,   Di-lower alkylaminocarbonyloxy lower alkyl group,   2-oxo-5-lower alkyl-1,3-dioxolen-4-ylmethyl group,  An optionally substituted piperidinyl carbonyloxy lower alkyl group, or  A compound, or a pharmaceutically acceptable salt thereof, characterized in that it represents a lower alkyl-lower cycloalkylaminocarbonyloxy-lower alkyl group. A compound according to claim 6, wherein R ⁴ represents an ethyl group, a 1- (cyclohexyloxycarbonyloxy) ethyl group, an acetoxymethyl group, a 1- (isopropyloxycarbonyloxy) ethyl group, 1- (ethoxycarbonyl Oxy) ethyl group, pivaloyloxymethyl group, cyclohexyloxycarbonyloxymethyl group, 1- (isobutyl oxycarbonyloxy) ethyl group, 1- (cyclohexyloxycarbonyloxy) -2-methylpropane-1- Diary, isobutyloxycarbonyloxymethyl group, isopropyloxycarbonyloxymethyl group, isobutyryloxymethyl group, (pentan-1-yl) oxycarbonyloxymethyl group, (butan-1-yl) oxycarbonyloxymethyl group, (1-ethylpropan-1-yl) oxycarbonyloxymethyl group, isopentyloxycarbonyloxymethyl group, (propan-1-yl) oxymethyl group, ethoxycarbonyloxymethyl group, neopentyloxycarbonyloxymethyl group, Oxycarbonyloxymethyl group, cyclopentyloxycarbonyloxymethyl group, t-butoxycarbonyloxyme Group, phthalidyl group, 1- (methoxycarbonyloxy) ethyl group, 1- (cyclopentyloxycarbonyloxy) ethyl group, (tetrahydropyran-4-yl) oxycarbonyloxymethyl group, 1- (neopentyloxy Carbonyloxy) ethyl group, (piperidin-1-yl) carbonyloxymethyl group, aryl group, 1- (t-butoxycarbonyloxy) ethyl group, N, N-di (propan-1-yl) aminocarbon Carbonyloxymethyl group, phenyloxycarbonyloxymethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group, (cis-2,6-dimethylpiperidin-1-yl) Carbonyloxymethyl group, N, N-di- (butan-1-yl) aminocarbonyloxymethyl group, hexane-1-yl group, N- (hexane-1-yl) -N-methylaminocarbonyloxymethyl group, N, N-diisobutylaminocarbonyloxymethyl group, N, N-diisopropylaminocarbonyloxymethyl group, N-cyclohexyl-N-methylaminocarbonyloxymethyl group, N-pentan-1-ylaminocarbonyloxymethyl group , N-cyclohexyl-N-ethylaminocarbonyloxymethyl group, N-isobutyl-N-isopropylaminocarbonyloxymethyl group, Nt-butyl-N-ethylaminocarbonyloxymethyl group, 1-[(cis-2,6-dimethylpiperidin-1-yl) carbonyloxy ] A compound characterized by showing an ethyl group, a 1- (N, N-diisopropylaminocarbonyloxy) ethyl group, or an N-ethyl-N-isoamylaminocarbonyloxymethyl group, or its pharmaceutically acceptable Possible salts. A compound of formula (III): or a pharmaceutically acceptable salt thereof:

[In the meal, One of R ^{2 ′} , and R ^{3 ′} is   Hydroxy lower alkyl group,   A hydroxy lower alkyl group protected by a protecting group of a hydroxy group,   Lower alkoxy-lower alkyl group, or   Lower alkoxycarbonyl group, And the other is a hydrogen atom, and R ⁵ represents a protecting group of a hydrogen atom or an alkyl group. The compound of claim 8, wherein, in formula (III), R ^{2 ′} , and R ^{3 ′} One of them,   Hydroxymethyl group,   Acetoxymethyl group,   Methoxycarbonyl group, or   Ethoxycarbonyl group, and Another is a hydrogen atom, or a pharmaceutically acceptable salt thereof. A compound of formula (IV): or a pharmaceutically acceptable salt thereof:

[In the meal, R ^{2 '} and R ^3' are the same or different, respectively,   Hydrogen atom,   Halogen atom,   Amino Group,   Substituted amino groups,   Hydroxy lower alkyl group,   Cyano lower alkyl group,   Lower alkoxy-lower alkyl groups,   Substituted lower alkoxy-lower alkyl group,   Lower alkoxy-lower alkoxy-lower alkyl groups,   Substituted lower alkoxy-lower alkoxy-lower alkyl group,   Acyloxy lower alkyl group,   Substituted acyloxy lower alkyl groups,   Carbamoyl,   Mono-lower alkylcarbamoyl groups,   Substituted mono-lower alkylcarbamoyl groups,   Di-lower alkylcarbamoyl groups,   Substituted di-lower alkylcarbamoyl groups,   Lower alkoxycarbonyl group,   Azetidinylcarbonyl group, or,   Substituted azetizinylcarbonyl group, and R ⁶ is R ⁷ -SC = C- , Where R ⁷ Represents a protecting group of a hydrogen atom, a metal ion, or a thiol. The compound of claim 10, wherein in formula (IV), R ^{2 ′} and R ^{3 ′} One of them,   Hydroxy lower alkyl group,   A hydroxy lower alkyl group protected by a protecting group of a hydroxy group,   Lower alkoxy-lower alkyl group, or   Lower alkoxycarbonyl group, and  Another is a hydrogen atom, or a pharmaceutically acceptable salt thereof. The compound of claim 11, wherein, in formula (IV), R ^{2 ′} and R ^{3 ′.} One of them,   Hydroxymethyl group,   Acetoxymethyl group,   Methoxycarbonyl group, or   Ethoxycarbonyl group, and Another is a hydrogen atom, or a pharmaceutically acceptable salt thereof. The compound of any one of claims 10-12, or a pharmaceutically acceptable salt thereof, characterized in that it has R ⁶ in position 5 of the thiazole ring of formula (IV). A process for preparing a compound of formula (I) according to claim 1, comprising reacting a compound of formula (V) with a compound of formula (IVc):

[In the meal, R ¹ represents a hydrogen atom or a methyl group, R ⁸ represents a protecting group of a hydrogen atom or a hydroxy group, R ⁹ represents a protecting group of a carboxyl group, L represents a leaving group;

[In the meal, R ^7c Represents a metal ion, R ^{2 '} and R ^3' are the same or different, respectively,   Hydrogen atom,   Halogen atom,   Amino Group,   Substituted amino groups,   Hydroxy lower alkyl group,   Cyano lower alkyl group,   Lower alkoxy-lower alkyl groups,   Substituted lower alkoxy-lower alkyl group,   Lower alkoxy-lower alkoxy-lower alkyl groups,   Substituted lower alkoxy-lower alkoxy-lower alkyl group,   Acyloxy lower alkyl group,   Substituted acyloxy lower alkyl groups,   Carbamoyl,   Mono-lower alkylcarbamoyl groups,   Substituted mono-lower alkylcarbamoyl groups,   Di-lower alkylcarbamoyl groups,   Substituted di-lower alkylcarbamoyl groups,   Lower alkoxycarbonyl group,   Azetidinylcarbonyl group, or,   Substituted azetidinylcarbonyl group]. The method according to claim 14, further comprising reacting a compound of formula (III) with a corresponding thiol represented by formula R ^7b SH to obtain a compound of formula (IVc):

[In the meal, R ^{2 '} And R ^{3 '} One of them,   Hydroxy lower alkyl group,   A hydroxy lower alkyl group protected by a protecting group of a hydroxy group,   Lower alkoxy-lower alkyl group, or   Lower alkoxycarbonyl group, and The other is a hydrogen atom, R ⁵ represents a protecting group of a hydrogen atom or an alkynyl group, and Wherein R ^7b in the corresponding thiol Is a group selected from the group consisting of a triphenylmethyl group, a diphenylmethyl group, an acyl protecting group, an optionally substituted benzyl group, and a silyl protecting group.] A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 16 or 17 for use as an antibacterial agent. A method of treating or preventing a bacterial infection or related symptoms thereof, comprising administering to a patient in need thereof an effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. . 20. The method of claim 19, wherein the bacterium associated with the bacterial infection is selected from the group consisting of pneumococci, influenza bacteria, catalcocci and β-lactamase acid bacteria. Way. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of bacterial infections or related symptoms thereof. 22. The use according to claim 21, wherein the bacterium associated with the bacterial infection is selected from the group consisting of pneumococci, influenza bacteria, catalcocci and β-lactamase acid bacteria.